Volume 1 - Number 1 May - September 1997
Volume 24 - Number 6 June 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.
It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.
See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf
Editorial correspondance
Jean-Loup Huret, MD, PhD, [email protected]
Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).
Publisher Contact: INIST-CNRS Mailing Address: Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France. Email Address:[email protected] Articles of the ATLAS are free in PDF format, and metadata are available on the web in Dublin Core XML format and freely harvestable.A Digital object identifier (DOI®), recorded at the International Agency CrossRefhttp://www.crossref.org/ is assigned to each article. http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Editors-in-Chief Jesús María Hernández Rivas (Salamanca, Spain) Paola Dal Cin (Boston, Massachusetts) Jean-Loup Huret (Poitiers, France) Hematology Section Editor Ana E. Rodríguez, Teresa Gonzalez (Salamanca, Spain) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Epigenetics Section Editor Roberto Piergentili (Rome, Italy) Hematopoeisis Section Editor Olga Weinberg (Boston, Massachusetts) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren, Barnabas Nyesiga (Malmö, Sweden) Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 François Desangles Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, Kessel The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research Oskar A. Haas Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Volume 24, Number 6, June 2020 Table of contents
Gene Section
HTR4 (5-hydroxytryptamine receptor 4) 224 Rafig Gurbanov, Hazel Karadag BIRC7 (baculoviral IAP repeat containing 7) 234 Dhiego Botelho Rigato, Paola Cristina Branco , Catarina Sofia Mateus Reis Silva, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo, Paula Christine Jimenez
Leukaemia Section del(5q) in acute lymphoblastic leukemia (ALL) 248 Adriana Zamecnikova, Soad al Bahar t(14;19)(q11;q13) TRA/NECTIN2 253 Jean Loup Huret t(14;19)(q32;q13) IGH/Various Partners 255 Jean Loup Huret
Case Report Section
B-cell acute lymphoblastic leukemia with t(2;9)(p11;p13) involving the immunoglobulin kappa locus (IGK) and PAX-5 259 Robert K McCall, Paula Moore, Nancy S,Rosenthal Angela G Niehaus, Bayard Powell, Pettenati Mark J KMT2A-CBL Fusion Gene Resulting from del(11)(q23.3q23.3) Identified by Chromosome Microarray Analysis - second report in AML 262 Temenuzhka Boneva and Elisabeth Nacheva Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review
HTR4 (5-hydroxytryptamine receptor 4) Rafig Gurbanov, Hazel Karadag Bilecik Seyh Edebali University, Department of Molecular Biology and Genetics Bilecik Seyh Edebali University, Biotechnology Application and Research Center; [email protected] (RG), Bilecik Seyh Edebali University, Department of Biotechnology, Bilecik Seyh Edebali University, Biotechnology Application and Research Center; [email protected] (HK), Turkey.
Published in Atlas Database: August 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/HTR4ID52727ch5q32.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70748/08-2019-HTR4ID52727ch5q32.pdf DOI: 10.4267/2042/70748
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Local order: Shown in Chromosome 5 - NC_000005.10 Reference GRCh38.p13 Primary Being a member of the serotonin receptor family, 5- Assembly. Cytogenetic Location of 5-HTR: 5q32, HT4 receptor ties up the neurotransmitter-serotonin which is the long (q) arm of chromosome 5 at a (5-hydroxytryptamine/ 5-HT) in the central nervous position 32 (UCSC Genome Browser on Human system (CNS) of mammals. Commonly 5-HT4 Dec. 2013 (GRCh38/hg38) Assembly) receptors (5-HTR4) are G-protein-coupled receptors (GPCRs), in which the G proteins cause the DNA/RNA induction of adenylate cyclase, subsequently leading to cyclic adenosine monophosphate (cAMP) and Note protein kinase A (PKA) activations. These receptors The 5-HTR4 gene is 172,607 bp long (according to are commonly expressed in gastrointestinal, UCSC, GRCh38/hg38), located on the minus (-) cardiovascular, nervous, and urinary systems, as strand and spans 12 exons (NCBI Homo sapiens well as the adrenal cortex (Tack et al., 2012). Annotation Release 109). In this review article, the genetic, cellular, and Transcription biochemical knowledge of 5-HT4 receptors is The gene has 13 transcripts (Table 1) deliberated. Besides the emphasis on receptor-ligand Protein interaction with therapeutics, the implication of Name Transcript ID bp Biotype (aa) these receptors in several health HTR4- Protein disturbances/diseases is considered on the basis of ENST00000360693.7 3082 428 201 coding available literature. HTR4- Protein ENST00000362016.6 2979 428 Keywords 202 coding 5-hydroxytryptamine receptor 4, Serotonin (5-HT), HTR4- Protein ENST00000377888.7 2962 388 Central Nervous System (CNS), Alzheimer's 203 coding Disease, Inflammatory Bowel Disease (IBD), HTR4- Protein ENST00000521530.5 1323 387 Obesity. 209 coding HTR4- Protein ENST00000521735.5 1242 378 Identity 210 coding HTR4- Protein Other names ENST00000520514.5 1236 411 207 coding 5-HT4, 5-HT4R HTR4- Protein ENST00000631296.1 1224 388 HGNC (Hugo): HTR4 213 coding Location: 5q32
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 224 HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
HTR4- Protein The Human Protein Atlas (http://www.
ENST00000517929.5 1201 360 204 coding proteinatlas.org) HTR4- Protein
ENST00000520086.1 2272 87 Function 206 coding Nonsense 5-hydroxytryptamine (5-HT or serotonin) is a crucial HTR4-
ENST00000522588.5 1326 378 mediated neurotransmitter of CNS with highly conserved 211 decay monoamine structure (Hodge et al., 2013). It plays a Nonsense role in different physiological events of CNS and HTR4-
ENST00000524063.3 2274 371 mediated 212 PNS by interacting with more than one receptor decay subtype (Cichon et al., 1998). These countless HTR4- No Processed functions are actualized by seven 5-HT subtype ENST00000519495.1 869 205 protein transcript receptors (Kroeze et al., 2002; Hodge et al., 2013). HTR4- No Retained The 5-HTR4 is a G-protein-coupled receptor that ENST00000521124.5 1221 208 protein intron arouses adenylate cyclase as a primary mode of Table 1. Transcripts of the human 5-HTR4 gene signal transduction. By the arousal of adenylate (Ensemble, GRCh38.p12). cyclase, the concentration of cAMP elevates (Lalut vd., 2017). However, 5-HTR4 refers to both G Protein protein-dependent and G protein-independent The product of HTR4 gene (5q32) is 5-HT4 receptor pathways (Figure 2a-b). The main G protein (Ohtsuki et al., 2002), weight as 43.761 Dalton with introduced by 5-HTR4 signaling is the Gs (shown in a length of 388 amino acids (Blondel et al., 1997; Figure 2a) that leads to the activation of the cAMP/ Claeysen et al., 1997; Van den Wyngaert et al., PKA pathway (Barthet et al., 2005). The G-protein 1997). The protein has 9 known isoforms produced independent non-canonical pathway activates Src by alternative splicing, but the potential isoforms (shown in Figure 2b) and subsequently ERK kinases, seem to exist (https://www.uniprot.org/ causing pERK1/ 2 phosphorylation (Barthet et al., uniprot/Q13639). Isoform 5-HT4(B) (Q13639-1) 2007). was considered as canonical sequence and provided This receptor was first described in primary cultures in Figure 1. The translated glycoprotein is a member of mouse embryonic colliculus neurons based on 5- of the serotonin receptor family which are induced in HT-induced cAMP production (Dumuis et al., response to the presence of serotonin via G-protein 1988). It plays potential roles in the physiology of coupling process. In general, the 5-HT4 receptor is a cardiovascular, urinary, and endocrine systems. It is glycosylated transmembrane protein expressed in also implicated in the pathophysiology of diseases both CNS and peripheric nervous system (PNS) that occurring in adrenal glands as well as urinary and acts as a modulator in the release of various gastrointestinal systems (Ford and Clarke., 1994). 5- neurotransmitters (NCBI). It expressed in various HTR4s are responsive in the events occurring in tissues/cells such as the brain, esophagus, ileum, adrenal glands, colon, cortex (Monferini et al.,1993), colon, bladder, heart, and adrenocortical cells. In the and atrial appendages (Kaumann et al., 1990, 1991; brain, they are particularly expressed in the Turconi et al., 1991; Quadid et al., 1992) of human hypothalamus, nucleus accumbens, amygdala, tissues by encouraging cAMPs. In turn, cAMP Calleja islands, olfactory tubercle, fundus striatum, inductions lead to steroid secretion in adrenal glands ventral pallidum, septum, hippocampus, and basal (Lefebvre et al., 1992) and circular muscle ganglia including substantia nigra (Bockaert et al., contraction in the colon (Tam et al.,1992). 2008). Therapeutic agents interacting with 5-HTR4 Advances in research on 5-HT set forward the development of therapeutics selectively interacting with 5-HT receptors. In the present day, these ligands mainly divided into 5 categories/classes. They are indoles including 5-HT analogs, indole carboxylates, and indole carboxamides, benzamides, benzoates, aryl ketones, and benzimidazoles (Bockaert et al., 2004). First-class 5-HTR4 agonists include substituted Figure 1. A canonical protein sequence (388 amino acids) of the human 5-HT4 receptor (PDB ID 5EM9.B) (Data was tryptamines or 5-HT agonists next to the substituted taken from the https://www.rcsb.org/pdb/protein/Q13639) triple-carbazimidamides. 5-MeOtryptamine is an interesting vehicle due to the lack of its affinity to 5- Expression HTR3 (Craig et al., 1990). The indole 5-HTR4 is expressed in different human carbazimidamide derivative, HTF 919 (Tegaserod), tissues/organs but mostly in gastrointestinal tract, has been found to be a potent partial agonist with brain, and muscles in descending order. Please see high affinity to 5-HTR4. In vivo studies show that
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 225
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
Tegaserod enhances gastrointestinal motor activity Naronapride, and Velusetrag) have therapeutic and adjusts impaired motility throughout the potential for patients with IBD. gastrointestinal tract. (Bockaert et al., 2004). These alternative drugs have a higher affinity for 5- Tegaserod is a benzamide derivative which was HTR4 compared to Tegaserod (Halland and Talley, approved by the FDA and other regulatory agencies 2013). YKP10811 is a mucosal partial agonist for the for the treatment of women with inflammatory 5-HTR4, induces serotonin release, initiates bowel disease (IBD) in which the constipation is peristaltic reflex, and has a low cardiovascular predominant or functional constipation (Tonini and adverse effect. Unlike traditional prokinetic drugs Pace 2006; Shin et al., 2015). such as Tegaserod, YKP10811 exhibits an However, it was later withdrawn from the market antinociceptive effect on inflammation as well as due to possible cardiovascular side-effects (Chey et acute stress-associated colonic hypersensitivity, and al., 2008; Thompson 2007). also considered as a candidate drug for IBD (Gilet et Three novel 5-HTR4 agonists (Prucaloprid, al., 2014).
Figure 2. A simplified pathway of G-protein dependent (a) and G-protein independent (b) signaling of 5-HTR4s (Modified from Bockaert et al., 2008)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 226
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
Figure 3. A simplified pathway showing release of 5-HT and it's interaction with 5-HTR4 in neuronal cells. Data were adopted and modified from KEGG: Kyoto Encyclopedia of Genes and Genomes (https://www.genome.jp/kegg/) in August 2019
The second class of 5-HTR4 agonists includes first- amyloid peptide formation in primary cortical generation benzamides carrying '2-methoxy-4- neurons (Cho and Hu, 2007). amino-5-chloro' substitution (Dumuis et al., 1989). Interestingly, RS 67333 produces a rapid These benzamides (zacopride, renzapride, and antidepressant effect after only three days of metoclopramide) were found to be non-selective and administration to rodents (Lucas et al., 2007). A always cause antagonistic activity at the 5-HTR3 more recent study comparing RS67333 with (Bockaert et al., 2004). antidepressant drug Fluoxetine (FLX) confirmed The third class of agonists, so-called benzoate that RS67333 causes anxiolytic-like effects after derivatives were deliberated with the replacement of only 7 days in several behavioral tests and that 5- benzamide's amide bond with an ester one, resulting HTR4 agonists produce faster effects than currently in increased affinity for 5-HTR4. The first partial and used antidepressants (Mendez-David et al., 2014). selective drug of this series is ML 10302, which has Another interesting agonist is a pyridine a high affinity for 5-HTR4 and poor affinity for other carboxamide, a cognitive drug (VRX-03011) for 5-HT receptor subtypes including 5-HTR3 (Langlois Alzheimer's disease (Bockaert et al., 2008). et al., 1994; Bockaert et al., 2004). Moser and Fifth class includes indoles such as GR 113808 with colleagues (2002) synthesized SL65.0155, a novel high affinity for 5-HTR4, and low affinity for 5- compound with high affinity for 5-HTR4. Being a HTR3 (Gale et al., 1994). Further, [3H] GR 113808 benzodioxane derivative, it is particularly effective is the first commercially available radioligand for 5- for learning and memory (Moser et al., 2002). HTR4 affinity studies (Grossman et al., 1993). SB The fourth class is consist of benzimidazoles (BIMU 203186 is an indole ester with potent and selective 8 and BIMU 1), which are potent and effective 5- 5-HTR4 antagonistic properties in various HTR4 agonists entering CNS (Dumuis et al., 1991; physiological assays, but the short half-life limits it's Rizzi et al., 1992). To overcome their metabolic in vivo application (Parker et al., 1993). variability, aryl ketones were prepared with 5-HTR4 In contrast, SB 207266 is a highly potent and ester ligands; instead of the ester linkage of the selective antagonist with a long duration of action antagonist RS 23597, a partial agonist RS 17017 was after oral administration (Gaster et al., 1995). SB synthesized, which has a similar affinity for 5-HTR4 207266 is a very useful vehicle in CNS studies (Clark et al., 1994). Increasing the size of the alkyl (Wardle et al., 1996; Gaster and King 1997). group led to an increase in the activity of the agonists Three selective and high-affinity 5-HTR4 RS 67333 and RS 67506 (Eglen et al., 1995). RS antagonists (GR 125487, SB 207266, and ML 67333, a selective 5-HTR4 partial agonist, is known 10375) have been reported to exhibit reverse to easily cross the blood-brain barrier. Systemic agonistic activity (Claeysen et al., 2000; Blondel et administration of selective 5-HT4 receptor partial al., 1998). agonists, like RS 67333 and RS 17017, enhances Roche Bioscience generated three potent 5-HTR4 rodent performance in olfactory relational learning reverse agonists, RO 116-2617, RO 116-0086, and (Marchetti et al., 2004), social-spatial memory tests RO 116-1148 (Joubert et al., 2002). 5-HTR4 ligands (Letty et al., 1997), and also improves delayed that may be of interest in CNS studies are listed in sample matching in young/ old macaques (Terry et Table 2. al., 1998). RS 67333 has been shown to inhibit β- Agonists Antagonists Reverse Antagonists 5-HT GR 113308 RO 116-2617
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 227
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
5-MeOT GF 125487 RO 116-0086 1999) and a stimulating effect on the hippocampus HTF919 SB 203186 RO 116-1148 to enhance memory and cognition (Bijak et al., 1997; Mohler et al., 2007). The absence of this receptor has Cisapride LY 353433 been found to impair stress-induced hypophagia and SC 53 116 SB 207 266 novelty-induced discovery efficiency in mice SB 205 149 SB 204070 (Compan et al., 2004a). The 5-HTR4 expression is Prucalopride RS 23597 also associated with the development of certain Mosapride ML 10375 behavioral characteristics of depression, like deletion or pharmacological blockade of 5-HTR4s Y-34959 ATBI 221 results in increased depressive and anxiety-like ML10302 RS 39606 behaviors in rodents (Carr and Lucki, 2011; Compan LS-65 0155 RS 67532 et al., 2004a; Conductier et al., 2006). Serotonin RS 67333 RS 100235 affects cardiac contraction by interacting with 5- RS 67506 RS 100302 HTR4 expressed in the human and porcine atrium and ventricle, interestingly, expressed only in the BUMI 1 atrium in the rat. 5-HTR4 activation causes cardiac BUMI 8 spasm as well as tachycardia and arrhythmia Table 2. 5-HTR4 ligands used in CNS studies (Qvigstad et al., 2005). This cardiac effect of 5- (Adopted from Bockaert et al., 2004). HTR4 is limited to human and porcine atria and are Homology not declared in other laboratory animals such as rats, guinea pigs, rabbits, and frogs. Moreover, 5-HTR4 Pairwise Aligment Scores activation triggers the release of acetylcholine in the Gene Identity (%) ileum of guinea pig and causes esophageal and Species Symbol Protein DNA colonic strictures (Hoyer et al., 2002). H.sapiens HTR4 Inflammatory bowel disease (IBD) vs. P.trogladytes HTR4 99,8 99,6 5-HTR4s which are widely expressed in the human vs. M.mulatta HTR4 98,6 98,1 intestine can also be expressed in inhibitory nitrergic vs. C.lupus HTR4 96,6 93,6 neurons to induce smooth muscle relaxation and vs. B.taurus HTR4 94,8 93,7 cholinergic neurons to control muscle contraction vs. M.musculus Htr4 93,3 90,9 (Bockaert et al., 2011; Hoffman et al., 2012). In vs. R. norvegicus Htr4 92,7 90,6 addition to their neuronal localization, they are found in enterocytes and enteroendocrine cells of the vs. G. gallus HTR4 88,5 82,6 intestinal mucosa that regulate fluid, mucus and 5- vs. X. tropicalis LOC100493952 83,4 74,5 HT secretion (Hoffman et al., 2012; Tonini, 2005). vs. D. rerio LOC556843 75,3 71,9 Accordingly, 5-HTR4s are attractive targets for the vs. D. melanogaster Oa2 47,5 54,3 treatment of IBD. The receptor agonists increase Table 3. Pairwise alignment of 5-HTR4 gene protein motility and accelerate transit from the gut, thereby sequences (in distance from human) (HomoloGene, NCBI). help in the alleviation of IBD and functional constipation (Halland and Talley, 2013). More Mutations selective 5-HTR4 agonists, including Naronapride (ATI-7505), Prucaloprid and Velusetrag (TD-5108), Somatic effectively target this receptor to support the A list of 5-HTR4 mutations in cancer can be found intestinal motility. However, the full mechanism of in COSMIC, the Catalogue Of Somatic Mutations In action of these compounds is not clearly resolved. Cancer, https://cancer.sanger.ac.uk/cosmic/gene/ One possibility is that 5-HTR4 agonists increase analysis?ln=HTR4. According to the Human Protein mobility by stimulating receptors on the enteric Atlas, HTR4 has been found strongly expressed in nerve terminals and increasing neurotransmitter prostate and endometrial cancers. release (Hoffman et al., 2012). A single nucleotide polymorphism (SNP) (rs201253747) c.* 61T>C in Implicated in HTR4 were identified in diarrhea-IBD patients (Wohlfarth et al., 2017). miRNAs can adjust HTR4 Animal Experiments 5-HTR4 was initially expression, and this regulation can be influenced identified in cultured mouse colliculus cells and either by the SNP c.*61 T>C or by lessened amounts guinea pig brain using a functional cAMP of miR-16 and miR-103 proposing the role HTR4 in stimulation assay (Dumuis et al., 1988). One of the the pathogenesis of IBD (Wohlfarth et al., 2017). oldest functions attributed to 5-HTR4 in rodents is Colonic biopsy specimens from patients with related to its role in increasing the release of Crohn's disease also showed greatly increased acetylcholine in the frontal cortex (Siniscalchi et al., mucosal 5-HTR4 expression (Shajib et al., 2018).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 228
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
Cardiac Disorders 1999). Animal studies showed that 5-HTR4 is involved in food intake. The genetic or 5-HTR4 is expressed in the atria and ventricles in pharmacological modifications of the receptor in humans; just like other serotonergic receptors, its pleasure-associated brain segments modulate food expression level is quite low under physiological intake as well (Haahr et al., 2012). It has been also state but may increase significantly in the case of reported that there is a strong positive correlation ventricular dysfunction. 5-HTR4 activation is known between body mass index (BMI) and 5-HTR4 to cause heart spasms, as well as tachycardia and concentrations in pleasure circuits (nucleus arrhythmia (Qvigstad et al., 2005). Even at low accumbens and ventral pallidum) controlling food expression levels, 5-HTR4 increases contraction intake, as well as in the left hippocampal region and strength (inotropic effect), accelerates early stage of orbitofrontal cortex. Therefore, stimulation of brain muscle relaxation (lusitropic effect) or enhances 5-HTR4s may be considered in the reduction of pulse rate (chronotropic effect) (De Maeyer et al., human hedonic overeating (Haahr et al., 2012). The 2008). Since 5-HT is a neurotransmitter responsible direct stimulation of 5-HTR4s in the nucleus for blood pressure regulation, peristaltic movements, accumbens reduces the physiological drive to eat and heart rate, and coagulation system, it acts on 5-HTR4 increases cocaine- and amphetamine-regulated in the human heart, producing a positive inotropic transcript (CART) mRNA levels in fed and food- effect on the stimulation of the atrium (Dorszewska deprived mice (Jean et al., 2007). The 5-HTR4 was et al., 2017). shown to regulate CART mRNA expression through Cushing's Syndrome cAMP/PKA signaling pathway. This receptor- 5-HTR4 has been shown to be overexpressed in the mediated upregulation of CART in the nucleus cortex of the adrenal gland in Cushing's syndrome, a accumbens triggers the appetite-suppressant effects disease that is caused by cortisone overproduction of ecstasy (Jean et al., 2007). The mechanisms (Cartier et al., 2003). In one study, cortisol secretion underlying feeding disorders in 5-HT4 receptor was encouraged with chorionic gonadotropin, knockout mice are related to a lesser efficacy of 5- luteinizing hormone, and 5-HTR4 stimulating drugs HT (hypothalamus, nucleus accumbens), leptin and in patients with Cushing's syndrome (Lacroix et al., the cocaine-amphetamine related transcript to reduce 1999). Long-term suppression of luteinizing food intake following stress (Compan et al., 2004b). hormone secretion by administering leuprolide These results show that 5-HTR4 plays an important acetate every four weeks led to a complete reversal role in nutritional behavior. of Cushing's syndrome (Lacroix et al., 1999). The Huntington's Disease administration of 5-HTR4 agonists such as Post-mortem brain samples of Huntington's disease metoclopramide, cisapride, and tegaserod stimulated patients revealed a 50% loss of 5-HTR4 in putamens aldosterone levels (Zwermann et al., 2009; Lefebvre (Reynolds et al., 1995). et al., 2002; Cartier et al., 2005). Specific 5-HTR4 antagonists such as GR 113808 are potent inhibitors Alzheimer's Disease of basal and/or cisapride-induced aldosterone Studies focused on neurodegenerative disorders such secretion (Lefebvre et al., 2002). as Alzheimer's disease associated with decreased Asthma expression of 5-HTR4 in the hippocampus and prefrontal cortex (Reynolds et al., 1995). Activation The 5-HTR4 gene is located in an area previously of 5-HTR4s stimulates acetylcholine release in the associated with an increased risk of Asthma and prefrontal cortex and hippocampus and improves Atopy (allergic diseases). Previously, 32 genetic learning and memory in various acquisition and variants in HTR4 consisting of 22 intronic SNPs, 2 memory paradigms (Cachard-Chastel et al., 2008; SNPs in the 3'-untranslated region (exon 7) and 8 Bockaert et al., 2011). These findings suggest that 5- SNPs in the 3'-downstream region were examined HTR4 agonists can be used to improve cholinergic (Kim et al., 2011). Logistic regression analysis function and cognition in Alzheimer's disease. The demonstrated the relationship between the 2 intronic impact of 5-HTR4s on the non-amyloidogenic polymorphisms with the risk of Asthma. Two minor metabolic pathway of the amyloid precursor protein HTR4 alleles, +142828G>A and +122769G>A, by stimulation of α-secretase has been described appeared at higher frequencies in the Asthma (Lezoualc'h and Robert, 2003; Cachard-Chastel et patients compared to healthy individuals. Therefore, al., 2007). Stimulation of 5-HTR4 triggers soluble SNP and haplotypes of the HTR4 gene have been amyloid precursor protein α (sAPPα) release and reported to be associated with the Asthma phenotype reduces amyloid-beta (aβ) peptide formation in (Kim et al., 2011). neuronal cell cultures (Maillet et al., 2003; Cho and Obesity Yu, 2007). A significant loss of 5-HTR4 was Obesity has been associated with chronic elevation observed in the hippocampus and frontal cortex of of brain serotonin levels in humans (Lambert et al., patients suffering from Alzheimer's disease. This
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 229
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
reduction in certain cerebral concentrations of 5- Barthet G, Framery B, Gaven F, Pellissier L, Reiter E, HTR4 has demonstrated its effects on cognitive Claeysen S, Bockaert J, Dumuis A. 5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated learning and memory processes and has been kinase pathway depends on Src activation but not on G recently described as a valuable target against protein or beta-arrestin signaling. Mol Biol Cell. 2007 Alzheimer's. (Lalut et al., 2017). 5-HTR4 receptor Jun;18(6):1979-91 agonists are known to improve memory deficits by Barthet G, Gaven F, Framery B, Shinjo K, Nakamura T, increasing acetylcholine neurotransmission Claeysen S, Bockaert J, Dumuis A. Uncoupling and (Consolo et al., 1994; Bockaert et al., 2011; Johnson endocytosis of 5-hydroxytryptamine 4 receptors. Distinct molecular events with different GRK2 requirements. J Biol et al., 2012). In a transgenic Alzheimer's mouse Chem. 2005 Jul 29;280(30):27924-34 model, stimulation of 5-HTR4 by agonists led to cognitive effects resulting in increased learning at Bijak M, Misgeld U. Effects of serotonin through serotonin1A and serotonin4 receptors on inhibition in the guinea-pig elevated levels of acetylcholine (Consolo et al., dentate gyrus in vitro. Neuroscience. 1997 Jun;78(4):1017- 1994; Baranger et al., 2017; Bockaert et al., 2011; 26 Brodney et al., 2012). In other words, 5-HTR4 Blondel O, Gastineau M, Langlois M, Fischmeister R. The stimulation improves performance in memory tasks 5-HT4 receptor antagonist ML10375 inhibits the constitutive in rodents, while receptor antagonists cause activity of human 5-HT4(c) receptor. Br J Pharmacol. 1998 performance deterioration in these tasks. In view of Oct;125(4):595-7 all this, 5-HTR4 activation may have beneficial Blondel O, Vandecasteele G, Gastineau M, Leclerc S, effects on Alzheimer's disease, both by preventing Dahmoune Y, Langlois M, Fischmeister R. Molecular and disease formation and by improving memory functional characterization of a 5-HT4 receptor cloned from performance (Rebholz et al., 2018). human atrium. FEBS Lett. 1997 Aug 4;412(3):465-74 Bockaert J, Claeysen S, Compan V, Dumuis A. 5-HT(4) Schizophrenia receptors, a place in the sun: act two Curr Opin Pharmacol Limited evidence suggests that 5-HTR4 2011 Feb;11(1):87-93 polymorphisms may be associated with Brodney MA, Johnson DE, Sawant-Basak A, Coffman KJ, susceptibility to Schizophrenia (Suzuki et al., 2003), Drummond EM, Hudson EL, Fisher KE, Noguchi H, attention deficit, and hyperactivity disorder (Li et al., Waizumi N, McDowell LL, Papanikolaou A, Pettersen BA, Schmidt AW, Tseng E, Stutzman-Engwall K, Rubitski DM, 2006). 5-HTR4 plays a role in cognitive function; Vanase-Frawley MA, Grimwood S. Identification of multiple that is assumed to be one of the main disorders of 5-HT partial agonist clinical candidates for the treatment of Schizophrenia. HTR4 coding regions were examined Alzheimer's disease J Med Chem 2012 Nov 8;55(21):9240- in 96 Japanese Schizophrenia patients. Within the 54 coding region, a silent SNP and six intronic SNPs Cachard-Chastel M, Devers S, Sicsic S, Langlois M, were detected and a significant relationship was Lezoualc'h F, Gardier AM, Belzung C. Prucalopride and donepezil act synergistically to reverse scopolamine- reported between Schizophrenia and haplotype A-T induced memory deficit in C57Bl/6j mice Behav Brain Res (Suzuki et al., 2003). 2008 Mar 5;187(2):455-61 Suicidal behavior Carr GV, Lucki I. The role of serotonin receptor subtypes in treating depression: a review of animal studies In a study evaluating the role of HTR4 on suicidal Psychopharmacology (Berl) 2011 Feb;213(2-3):265-87 behavior, significantly high levels of 5-HTR4 and cAMP were found in the frontal cortex and caudate Cartier D, Jégou S, Parmentier F, Lihrmann I, Louiset E, Kuhn JM, Bastard C, Plouin PF, Godin M, Vaudry H, nucleus of the depressed suicide victims (Rosel et al., Lefebvre H. Expression profile of serotonin4 (5-HT4) 2004). Another secondary messenger 5-HTR4, receptors in adrenocortical aldosterone-producing 1,4,5-inositol triphosphate (IP3) were elevated in the adenomas Eur J Endocrinol 2005 Dec;153(6):939-47 caudate nucleus and hippocampus, whereas no Cartier D, Lihrmann I, Parmentier F, Bastard C, Bertherat J, changes were observed in these parameters in the Caron P, Kuhn JM, Lacroix A, Tabarin A, Young J, Vaudry amygdala region. The caudate nucleus appears as the H, Lefebvre H. Overexpression of serotonin4 receptors in most affected brain site on account of the significant cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing changes in the serotonergic system and thereby is Cushing's syndrome J Clin Endocrinol Metab 2003 important in terms of diagnostic sensitivity (Rosel et Jan;88(1):248-54 al., 2004). Chey WD, Paré P, Viegas A, Ligozio G, Shetzline MA. Tegaserod for female patients suffering from IBS with mixed References bowel habits or constipation: a randomized controlled trial Am J Gastroenterol 2008 May;103(5):1217-25 Baranger K, Giannoni P, Girard SD, Girot S, Gaven F, Stephan D, Migliorati M, Khrestchatisky M, Bockaert J, Cho S, Hu Y. Activation of 5-HT4 receptors inhibits Marchetti-Gauthier E, Rivera S, Claeysen S, Roman FS. secretion of beta-amyloid peptides and increases neuronal survival Exp Neurol 2007 Jan;203(1):274-8 Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and Cichon S, Kesper K, Propping P, Nöthen MM. Assignment memory deficits in the 5xFAD mouse model of Alzheimer's of the human serotonin 4 receptor gene (HTR4) to the long disease. Neuropharmacology. 2017 Nov;126:128-141 arm of chromosome 5 (5q31-q33) Mol Membr Biol 1998 Apr-Jun;15(2):75-8
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 230
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
Claeysen S, Sebben M, Bécamel C, Eglen RM, Clark RD, inflammation Neurogastroenterol Motil 2014 Bockaert J, Dumuis A. Pharmacological properties of 5- Dec;26(12):1761-70 Hydroxytryptamine(4) receptor antagonists on constitutively active wild-type and mutated receptors Mol Pharmacol Grossman CJ, Kilpatrick GJ, Bunce KT. Development of a 2000 Jul;58(1):136-44 radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain Br J Pharmacol 1993 Jul;109(3):618-24 Compan V, Charnay Y, Dusticier N, Daszuta A, Hen R, Bockaert J. [Feeding disorders in 5-HT4 receptor knockout Haahr ME, Rasmussen PM, Madsen K, Marner L, Ratner C, mice] J Soc Biol 2004;198(1):37-49 Gillings N, Baaré WF, Knudsen GM. Obesity is associated with high serotonin 4 receptor availability in the brain Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, reward circuitry Neuroimage 2012 Jul 16;61(4):884-8 Gingrich J, Dumuis A, Brunner D, Bockaert J, Hen R. Attenuated response to stress and novelty and Halland M, Talley NJ. New treatments for IBS Nat Rev hypersensitivity to seizures in 5-HT4 receptor knock-out Gastroenterol Hepatol 2013 Jan;10(1):13-23 mice J Neurosci 2004 Jan 14;24(2):412-9 Hodge E, Nelson CP, Miller S, Billington CK, Stewart CE, Conductier G, Dusticier N, Lucas G, Côté F, Debonnel G, Swan C, Malarstig A, Henry AP, Gowland C, Melén E, Hall Daszuta A, Dumuis A, Nieoullon A, Hen R, Bockaert J, IP, Sayers I. HTR4 gene structure and altered expression Compan V. Adaptive changes in serotonin neurons of the in the developing lung Respir Res 2013 Jul 26;14:77 raphe nuclei in 5-HT(4) receptor knock-out mouse Eur J Hoffman JM, Tyler K, MacEachern SJ, Balemba OB, Neurosci 2006 Aug;24(4):1053-62 Johnson AC, Brooks EM, Zhao H, Swain GM, Moses PL, Consolo S, Arnaboldi S, Giorgi S, Russi G, Ladinsky H. 5- Galligan JJ, Sharkey KA, Greenwood-Van Meerveld B, HT4 receptor stimulation facilitates acetylcholine release in Mawe GM. Activation of colonic mucosal 5-HT(4) receptors rat frontal cortex Neuroreport 1994 Jun 2;5(10):1230-2 accelerates propulsive motility and inhibits visceral hypersensitivity Gastroenterology 2012 Apr;142(4):844- Craig DA, Eglen RM, Walsh LK, Perkins LA, Whiting RL, 854 Clarke DE. 5-Methoxytryptamine and 2-methyl-5- hydroxytryptamine-induced desensitization as a Hoyer D, Hannon JP, Martin GR. Molecular, discriminative tool for the 5-HT3 and putative 5-HT4 pharmacological and functional diversity of 5-HT receptors receptors in guinea pig ileum Naunyn Schmiedebergs Arch Pharmacol Biochem Behav 2002 Apr;71(4):533-54 Pharmacol 1990 Jul;342(1):9-16 Johnson DE, Drummond E, Grimwood S, Sawant-Basak A, De Maeyer JH, Lefebvre RA, Schuurkes JA. 5-HT4 receptor Miller E, Tseng E, McDowell LL, Vanase-Frawley MA, agonists: similar but not the same Neurogastroenterol Motil Fisher KE, Rubitski DM, Stutzman-Engwall KJ, Nelson RT, 2008 Feb;20(2):99-112 Horner WE, Gorczyca RR, Hajos M, Siok CJ. The 5- hydroxytryptamine4 receptor agonists prucalopride and Dorszewska J, Florczak-Wyspianska J, Kowalska M, PRX-03140 increase acetylcholine and histamine levels in Stanski M, Kowalewska A, Kozubski W.. Serotonin in the rat prefrontal cortex and the power of stimulated Neurological Diseases. Additional information is available at hippocampal oscillations J Pharmacol Exp Ther 2012 the end of the chapter, 2017 Jun;341(3):681-91 Dumuis A, Bouhelal R, Sebben M, Cory R, Bockaert J. A Joubert L, Claeysen S, Sebben M, Bessis AS, Clark RD, nonclassical 5-hydroxytryptamine receptor positively Martin RS, Bockaert J, Dumuis A. A 5-HT4 receptor coupled with adenylate cyclase in the central nervous transmembrane network implicated in the activity of inverse system Mol Pharmacol 1988 Dec;34(6):880-7 agonists but not agonists J Biol Chem 2002 Jul 12;277(28):25502-11 Dumuis A, Sebben M, Monferini E, Nicola M, Turconi M, Ladinsky H, Bockaert J. Azabicycloalkyl benzimidazolone Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ. derivatives as a novel class of potent agonists at the 5-HT4 A 5-HT4-like receptor in human right atrium Naunyn receptor positively coupled to adenylate cyclase in brain Schmiedebergs Arch Pharmacol 1991 Aug;344(2):150-9 Naunyn Schmiedebergs Arch Pharmacol 1991 Mar;343(3):245-51 Kim TH, An SH, Cha JY, Shin EK, Lee JY, Yoon SH, Lee YM, Uh ST, Park SW, Park JS, Kim YH, Choi JS, Lee SO, Eglen RM, Bonhaus DW, Johnson LG, Leung E, Clark RD. Park BL, Shin HD, Park CS. Association of 5- Pharmacological characterization of two novel and potent 5- hydroxytryptamine (serotonin) receptor 4 (5-HTR4) gene HT4 receptor agonists, RS 67333 and RS 67506, in vitro polymorphisms with asthma Respirology 2011 and in vivo Br J Pharmacol 1995 Aug;115(8):1387-92 May;16(4):630-8 Gale JD, Grossman CJ, Whitehead JW, Oxford AW, Bunce Kroeze WK, Kristiansen K, Roth BL. Molecular biology of KT, Humphrey PP. GR113808: a novel, selective antagonist serotonin receptors structure and function at the molecular with high affinity at the 5-HT4 receptor Br J Pharmacol 1994 level Curr Top Med Chem 2002 Jun;2(6):507-28 Jan;111(1):332-8 Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy Gaster LM, Joiner GF, King FD, Wyman PA, Sutton JM, in luteinizing hormone--dependent Cushing's syndrome N Bingham S, Ellis ES, Sanger GJ, Wardle KA. N-[(1-butyl-4- Engl J Med 1999 Nov 18;341(21):1577-81 piperidinyl)methyl]-3,4dihydro-2H-[1,3]oxazino[3,2- a]indole10-carboxamide hydrochloride: the first potent and Lalut J, Karila D, Dallemagne P, Rochais C. Modulating 5- selective 5-HT4 receptor antagonist amide with oral activity HT(4) and 5-HT(6) receptors in Alzheimer's disease J Med Chem 1995 Nov 24;38(24):4760-3 treatment Future Med Chem 2017 May;9(8):781-795 Gaster LM, King FD. Serotonin 5-HT3 and 5-HT4 receptor Lambert GW, Vaz M, Cox HS, Turner AG, Kaye DM, antagonists Med Res Rev 1997 Mar;17(2):163-214 Jennings GL, Esler MD. Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover Gilet M, Eutamene H, Han H, Kim HW, Bueno L. Influence Clin Sci (Lond) 1999 Feb;96(2):191-7 of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and Langlois M, Zhang L, Yang D, Bremont B, Shen S, Manara L, Croci T.. Design of a potent 5-HT4 receptor agonist with nanomolar affinity. Bioorg. Med. Chem. Lett., 1994 ; 4, 1433
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 231
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
Lefebvre H, Cartier D, Duparc C, Lihrmann I, Contesse V, Qvigstad E, Brattelid T, Sjaastad I, Andressen KW, Krobert Delarue C, Godin M, Fischmeister R, Vaudry H, Kuhn JM. KA, Birkeland JA, Sejersted OM, Kaumann AJ, Skomedal Characterization of serotonin(4) receptors in adrenocortical T, Osnes JB, Levy FO. Appearance of a ventricular 5-HT4 aldosterone-producing adenomas: in vivo and in vitro receptor-mediated inotropic response to serotonin in heart studies J Clin Endocrinol Metab 2002 Mar;87(3):1211-6 failure Cardiovasc Res 2005 Mar 1;65(4):869-78 Letty S, Child R, Dumuis A, Pantaloni A, Bockaert J, Rebholz H, Friedman E, Castello J. Alterations of Rondouin G. 5-HT4 receptors improve social olfactory Expression of the Serotonin 5-HT4 Receptor in Brain memory in the rat Neuropharmacology 1997 Apr-May;36(4- Disorders Int J Mol Sci 2018 Nov 13;19(11) 5):681-7 Reynolds GP, Mason SL, Meldrum A, De Keczer S, Parnes Lezoualc'h F, Robert SJ. The serotonin 5-HT4 receptor and H, Eglen RM, Wong EH. 5-Hydroxytryptamine (5-HT)4 the amyloid precursor protein processing Exp Gerontol receptors in post mortem human brain tissue: distribution, 2003 Jan-Feb;38(1-2):159-66 pharmacology and effects of neurodegenerative diseases Br J Pharmacol 1995 Mar;114(5):993-8 Li J, Wang Y, Zhou R, Wang B, Zhang H, Yang L, Faraone SV. Association of attention-deficit/hyperactivity disorder Rizzi CA, Coccini T, Onori L, Manzo L, Tonini M. with serotonin 4 receptor gene polymorphisms in Han Benzimidazolone derivatives: a new class of 5- Chinese subjects Neurosci Lett 2006 Jun 19;401(1-2):6-9 hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum J Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta Pharmacol Exp Ther 1992 May;261(2):412-9 S, Lambas-Senas L, Wiborg O, Haddjeri N, Piñeyro G, Sadikot AF, Debonnel G. Serotonin(4) (5-HT(4)) receptor Shajib S, Chauhan Usha, Adeeb S, Chetty Y, Armstrong D, agonists are putative antidepressants with a rapid onset of Smita LS, Halder J.. Characterization of Serotonin Signaling action Neuron 2007 Sep 6;55(5):712-25 Components in Patients with Inflammatory. Journal of the Canadian Association of Gastroenterology, 2018. Maillet M, Robert SJ, Cacquevel M, Gastineau M, Vivien D, Bertoglio J, Zugaza JL, Fischmeister R, Lezoualc'h F. Shin A, Acosta A, Camilleri M, Boldingh A, Burton D, Ryks Crosstalk between Rap1 and Rac regulates secretion of M, Rhoten D, Zinsmeister AR. A randomized trial of 5- sAPPalpha Nat Cell Biol 2003 Jul;5(7):633-9 hydroxytryptamine4-receptor agonist, YKP10811, on colonic transit and bowel function in functional constipation Marchetti E, Chaillan FA, Dumuis A, Bockaert J, Soumireu- Clin Gastroenterol Hepatol 2015 Apr;13(4):701-8 Mourat B, Roman FS. Modulation of memory processes and cellular excitability in the dentate gyrus of freely moving rats Siniscalchi A, Badini I, Beani L, Bianchi C. 5-HT4 receptor by a 5-HT4 receptors partial agonist, and an antagonist modulation of acetylcholine outflow in guinea pig brain Neuropharmacology 2004 Dec;47(7):1021-35 slices Neuroreport 1999 Feb 25;10(3):547-51 Mendez-David I, David DJ, Darcet F, Wu MV, Kerdine- Suzuki T, Iwata N, Kitamura Y, Kitajima T, Yamanouchi Y, Römer S, Gardier AM, Hen R. Rapid anxiolytic effects of a Ikeda M, Nishiyama T, Kamatani N, Ozaki N. Association of 5-HT receptor agonist are mediated by a neurogenesis- a haplotype in the serotonin 5-HT4 receptor gene (HTR4) independent mechanism Neuropsychopharmacology 2014 with Japanese schizophrenia Am J Med Genet B May;39(6):1366-78 Neuropsychiatr Genet 2003 Aug 15;121B(1):7-13 Mohler EG, Shacham S, Noiman S, Lezoualc'h F, Robert S, Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy Gastineau M, Rutkowski J, Marantz Y, Dumuis A, Bockaert BE, Müller-Lissner S, Quigley EM, Schuurkes J, De Maeyer J, Gold PE, Ragozzino ME. VRX-03011, a novel 5-HT4 JH, Stanghellini V. Systematic review: cardiovascular safety agonist, enhances memory and hippocampal acetylcholine profile of 5-HT(4) agonists developed for gastrointestinal efflux Neuropharmacology 2007 Sep;53(4):563-73 disorders Aliment Pharmacol Ther 2012 Apr;35(7):745-67 Monferini E, Gaetani P, Rodriguez y Baena R, Giraldo E, Tam FS, Hillier K, Bunce KT. Characterization of the 5- Parenti M, Zocchetti A, Rizzi CA. Pharmacological hydroxytryptamine receptor type involved in inhibition of characterization of the 5-hydroxytryptamine receptor spontaneous activity of human isolated colonic circular coupled to adenylyl cyclase stimulation in human brain Life muscle Br J Pharmacol 1994 Sep;113(1):143-50 Sci 1993;52(9):PL61-5 Terry AV Jr, Buccafusco JJ, Jackson WJ, Prendergast MA, Moser PC, Bergis OE, Jegham S, Lochead A, Duconseille Fontana DJ, Wong EH, Bonhaus DW, Weller P, Eglen RM. E, Terranova JP, Caille D, Berque-Bestel I, Lezoualc'h F, Enhanced delayed matching performance in younger and Fischmeister R, Dumuis A, Bockaert J, George P, Soubrié older macaques administered the 5-HT4 receptor agonist, P, Scatton B. SL65 0155, a novel 5-hydroxytryptamine(4) RS 17017 Psychopharmacology (Berl) 1998 receptor partial agonist with potent cognition-enhancing Feb;135(4):407-15 properties J Pharmacol Exp Ther Thompson CA. Novartis suspends tegaserod sales at FDA's Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, Toyota T, request Am J Health Syst Pharm 2007 May 15;64(10):1020 Shimizu H, Yamada K, Yoshitsugu K, Hattori E, Yoshikawa T, Arinami T. Association between serotonin 4 receptor Tonini M. 5-Hydroxytryptamine effects in the gut: the 3, 4, gene polymorphisms and bipolar disorder in Japanese and 7 receptors Neurogastroenterol Motil 2005 case-control samples and the NIMH Genetics Initiative Oct;17(5):637-42 Bipolar Pedigrees Mol Psychiatry 2002;7(9):954-61 Tonini M, Pace F. Drugs acting on serotonin receptors for Ouadid H, Seguin J, Dumuis A, Bockaert J, Nargeot J. the treatment of functional GI disorders Dig Dis 2006;24(1- Serotonin increases calcium current in human atrial 2):59-69 myocytes via the newly described 5-hydroxytryptamine4 Turconi M, Schiantarielli P, Borsini F, Rizzi C A, Ladinsky H, receptors Mol Pharmacol 1992 Feb;41(2):346-51 Donepti A.. Azabicycloalkyl benzimidazolones: interaction Parker SG, HHamburger S, Taylor EM, Kaumann AJ.. with serotonergic 5-HT3 and 5-HT4 receptors and potential SB203186, a potent 5-HT4 receptor antagonist in porcine therapeutic implications. Drugs Future, 1991 ; 16: 1011- sinoatrial node and human and porcine atrium. Br. 1026. J.Pharmacol, 1993 ; 108, 68p.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 232
HTR4 (5-hydroxytryptamine receptor 4) Gurbanov R, Karadag H
Van den Wyngaert I, Gommeren W, Verhasselt P, Jurzak HT(4) receptor signalling and correlate with symptom profile M, Leysen J, Luyten W, Bender E. Cloning and expression in irritable bowel syndrome Sci Rep 2017 Oct of a human serotonin 5-HT4 receptor cDNA J Neurochem 31;7(1):14680 1997 Nov;69(5):1810-9 Zwermann O, Suttmann Y, Bidlingmaier M, Beuschlein F, Wardle KA, Bingham S, Ellis ES, Gaster LM, Rushant B, Reincke M. Screening for membrane hormone receptor Smith MI, Sanger GJ. Selective and functional 5- expression in primary aldosteronism Eur J Endocrinol 2009 hydroxytryptamine4 receptor antagonism by SB 207266 Br Mar;160(3):443-51 J Pharmacol 1996 Jun;118(3):665-70 This article should be referenced as such: Wohlfarth C, Schmitteckert S, Härtle JD, Houghton LA, Dweep H, Fortea M, Assadi G, Braun A, Mederer T, Pöhner Gurbanov R, Karadag H. HTR4 (5-hydroxytryptamine S, Becker PP, Fischer C, Granzow M, Mönnikes H, Mayer receptor 4). Atlas Genet Cytogenet Oncol Haematol. EA, Sayuk G, Boeckxstaens G, Wouters MM, Simrén M, 2020; 24(6):224-233. Lindberg G, Ohlsson B, Schmidt PT, Dlugosz A, Agreus L, Andreasson A, D'Amato M, Burwinkel B, Bermejo JL, Röth R, Lasitschka F, Vicario M, Metzger M, Santos J, Rappold GA, Martinez C, Niesler B. miR-16 and miR-103 impact 5-
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 233
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Gene Section Review
BIRC7 (baculoviral IAP repeat containing 7) Dhiego Botelho Rigato, Paola Cristina Branco , Catarina Sofia Mateus Reis Silva, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo, Paula Christine Jimenez Department of Marine Science, Institute of Marine Sciences, Federal University of São Paulo, Santos, Brazil (DBR, PCJ); Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil (PCB, CSMRS, JAMN, LVCL); [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]
Published in Atlas Database: September 2019
Online updated version : http://AtlasGeneticsOncology.org/Genes/BIRC7ID799ch20q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70749/09-2019-BIRC7ID799ch20q13.pdf DOI: 10.4267/2042/70749
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Laryngeal cancer; Leukemia; Hepatocellular Abstract carcinoma; Lung cancer; Lymphoma; Melanoma; BIRC7, also known as livin, is a member of the Mesothelioma; Oral squamous cell carcinoma; Inhibitor of Apoptosis Protein (IAP) family and is Ovarian cancer; Osteosarcoma; Pancreas cancer; linked to the prevention of cell death induced by Prostate cancer; Retinocytoma; Urinary tract cancer apoptosis, by directly or indirectly preventing caspase activity. In general, as most IAPs, BIRC7 Identity expression is not detectable in normal differentiated Other names adult tissues, with the exception of placenta, spleen, lymph nodes and developing embryonic tissues. On ML-IAP, KIAP, RNF50, Livin, melanoma inhibitor the other hand, BIRC7 overexpression has been of apoptosis protein, kidney inhibitor of apoptosis reported in a variety of tumor types, in which it is protein, livin inhibitor-of-apoptosis associated to malignancy and chemoresistance. HGNC (Hugo): BIRC7 Currently, there are some unanswered questions Location: 20q13.3 about BIRC7, including its interaction with caspases, a potential paradoxical role in the apoptotic process, DNA/RNA and specific functions/affinities of the BIRC7α and BIRC7β splice variants. Moreover, several studies Description have demonstrated the value of BIRC7 as a The BIRC7 gene is about 4.6 Kb (start: 63235883 bp therapeutic target in a number of cancer types. This and end: 63240507 bp; orientation: plus strand). review mainly focuses on the role of BIRC7 in There are two transcript variants deposited in the cancer cell biology and its clinical significance, NCBI database demonstrating aspects of its DNA/RNA and protein, (https://www.ncbi.nlm.nih.gov/gene). The transcript as well as its relevance in cancer diagnosis and variant 1 (cDNA: 1334 bp) encodes the longer prognosis. isoform (alpha; BIRC7α) (298 aa). The transcript Keywords variant 2 (cDNA: 1280 bp) presents an alternate in- BIRC7; Interact with caspases; Apoptosis; Breast frame splice site and encodes the shorter isoform cancer; Ampullary carcinoma; Neuroblastoma; (beta; BIRC7β) (280 aa). Isoform α blocks Glioblastoma; Cervical carcinoma; Colorectal staurosporine-induced apoptosis and augments cancer; Esophageal carcinoma; Gastric cancer; Head killing by natural killer (NK) cells, while isoform β and neck squamous cell carcinoma; Kidney cancer; blocks etoposide-induced apoptosis and protects
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 234 BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
against NK cell. There is an additional transcript (BIRC1), cIAP1 ( BIRC2), cIAP2 ( BIRC3), XIAP variant reported in Ensembl (BIRC4), survivin ( BIRC5), Apollon/Bruce ( (http://www.ensembl.org/), which contains a cDNA BIRC6), livin/ML-IAP (BIRC7) e ILP-2 ( BIRC8), of 593 bp, and generates a protein with 193 aa. and these may present either one or three BIR domains arranged in their N-terminal portion Protein (Budhidarmo & Day, 2015; Deveraux & Reed, 1999; Lopez Meier, 2010). Description BIRC7 is a 39 kDa member of the IAP family, The IAPs (Inhibitors of Apoptosis Proteins) are a structured with a single BIR domain, added with a family of proteins recognized, predominantly, for RING domain on the C-terminus portion, as firstly their role in preventing apoptotic cell death by described by Vucic and colleagues in the year 2000 directly or indirectly hindering caspase activity. (Figure 1). Its BIR domain is globularly assembled, Nevertheless, these proteins are further involved in with four α-helixes and a three-strand anti-parallel β- other signaling pathways associated to cell survival, sheet (Hinds et al., 1999). In turn, the RING-type cell cycle and cell migration (Gyrd-Hansen & Meier, zinc-finger domain, alike in other RING-bearing 2010; Owens et al., 2013; Plati, Bucur Khosravi-Far, IAPs, has ubiquitin-ligase (E3) activity and, thus, is 2011). The presence of, at least, one BIR domain associated with the ubiquitination functionality; (baculovirus IAP repeat), a conserved sequence of however further studies have demonstrated about 80 amino acid residues with Zn+2 in the center, additional and yet unclear roles in addressing which mediates the protein-protein interactions with apoptotic activity (Ma et al., 2006). caspases being essential for their anti-apoptotic A distinctive feature of this protein is that, unlike any activity, is the structural distinctive of the family other IAP, following a strong apoptotic incitement, (Budhidarmo & Day, 2015; Deveraux & Reed, 1999; BIRC7 is cleaved by CASP3 and CASP7 (caspases- Lopez; Meier, 2010). Eight IAPs have been 3 and -7) at Asp52 to give a truncated form, which, identified within the human proteome - NAIP paradoxically, promotes cell death (Nachmias et al., 2003).
Figure 1. Structure of BIRC7 and its variants. BIRC7 (also known as livin) protein structure has 39 kDa and is composed of a single BIR domain containing approximately 70 amino acids (aa) and zinc binding residues. The protein nucleus is generally connected with a conserved cysteine and is rich in histidine, and is connected to its anti-apoptotic activity. Additionally, the RING domain, which gene covers 4.6 kb in chromosome 20, band q13, is composed by six introns and seven exons. Structurally, BIRC7-BIR forms a globular architecture preserved by four α-helices and an anti-parallel sheet of three filaments, as well as residues that form the hydrophobic nucleus. The RING domain is usually defined by seven cysteines and a histidine that can coordinate two zinc atoms in its carboxy terminal. BIRC7 has two similar variants, α and β, differing by 18 amino acids located between the BIR and RING domains, present only in the isoform α. Both isoforms have shown biological relevance to cancer.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 235
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
By such trait, rather than merely an apoptosis death activity of the truncated forms of the protein inhibitor, BIRC7 may actually be allowed to a (Gong et al., 2005; Lazar et al., 2012). broader title, one of a cell death regulator. Gastric, prostate, bladder, breast, renal and liver Furthermore, through alternative splicing of the carcinomas, along with neuroblastoma, leukemia, mRNA, BIRC7 has two splice variants, BIRC7α and and lymphomas, as well as non-small cell lung, BIRC7β, which have different subcellular cervical, liver and pancreatic cancers have all been distribution and distinct anti-apoptosis properties. related to BIRC7 upregulation (Gazzaniga et al., Still, the BIR and RING domains are identical in 2003; Tanabe et al., 2004; Hariu et al., 2005; Kim et both isoforms, and their only structural difference is al., 2005; Wagener et al., 2007; Augello et al., 2009; assumed by the 18 amino acids present between Yuan et al., 2009; Wang et al., 2010; El-Mesallamy these domains in the α isoform, allowing the et al., 2011; Lazar et al., 2012). In neuroblastoma, formation of an α-helix linker (Ashhab et al., 2001; bladder and gastric cancers, higher levels of BIRC7 Li et al., 2013a). expression could be pondered as a risk factor, once For BIRC7, there are currently a number of isoform α, but not β, was predominant in bladder unanswered questions concerning the protein cancerous tissue but neither isoform occurred in the interaction with caspases, the paradoxical activities healthy tissue (Gazzaniga et al., 2003). In gastric it can undertake during apoptosis and, also, on cancer, nearly half of the assessed patients expressed specific functions and affinities of the α and β both isoforms in their tumorous tissue, however variants. Still, taken the range of activities and benign gastric lesions showed no detectable BIRC7 regulatory motifs of the protein, BIRC7 has been expression (Wang et al., 2010). regarded as an interesting target for cancer therapy. Moreover, Ashhab and colleagues (2001) assessed As this IAP displays such unique pro- and anti- mRNA transcripts of BIRC7α and BIRC7β in a apoptotic properties, a treatment strategy could panel of human tumor cell lines and upregulation of involve the promotion of BIRC7 cleavage, directing both isoforms was detected in melanoma, colon, and accumulation of the truncated protein, in an attempt prostate carcinoma cells. Nevertheless, when to tip the scale towards the pro-apoptotic effect, to measured in normal fetal and adult tissues, different counteract apoptosis resistance promoted by IAPs expression levels for each isoform suggests a and other disrupted signaling pathways present in specific pattern of splicing and expression related to cancer cells (Wang et al., 2008). Other therapeutic histology. Notable levels of BIRC7β were found opportunities include targeting BIRC7 at the mainly in fetal kidney, spleen, and heart, whereas no transcriptional level using antisense BIRC7α was detected in fetal tissues. Adult tissues, oligonucleotides, thus, reducing the expression such as heart, placenta, lung, spleen and ovary levels of the protein. Interestingly, antisense IAP showed upregulation of both isoforms, while only therapy is also under clinical testing for XIAP and the α isoform was detected in brain, skeletal muscle BIRC5, with promising candidates (Xia et al., 2002; and lymphocytes (Ashhab et al., 2001). Hu et al., 2003). Localisation Expression BIRC7 can be found both in the nucleus and in the Much like most IAPs, BIRC7 has low or even no cytoplasm, and the localization of this IAP has been detectable expression in normal differentiated adult compared to that of BIRC5 (Kasof Gomes, 2001). tissues, but is present in high levels in placenta, Nevertheless, full-length forms of both BIRC7 spleen, lymph nodes, developing/embryonic tissues variants are present exclusively in the cytoplasm, and in a variety of tumor types (Li et al., 2013a). In while a peri-nuclear distribution is seen for the pro- fact, BIRC7 overexpression has been recorded in apoptotic truncated forms of BIRC7 (t-livin), with numerous cancers, however, it is best linked to the prominent accumulation in the Golgi apparatus malignancy in which it was preferentially (Nachmias et al., 2007a). In fact, subcellular overexpressed when it was originally detected - localization has been known to regulate the different melanoma -, justifying the attributed label of ML- roles of IAPs in the apoptosis process (Ambrosini et IAP (melanoma inhibitor of apoptosis proteins) al., 1998). In this context, Nachmias and colleagues (Vucic et al., 2000). BIRC7 protein levels have been (2007) have demonstrated that the N-terminal region found upregulated in primary tumors as well as in of t-livin directs the peri-nuclear distribution and this various melanoma cell lines, whereas it was only arrangement is essential, but not enough, to give t- detectable in negligible amounts in melanocytes or livin its pro-apoptotic activity. The RING domain, nevi. Still, in melanoma, high levels of BIRC7 have whose purposes have been afflicted with much been associated to chemoresistance and poor ambiguity among distinct IAPs, then fulfills the prognosis, while intermediate levels (but not operative role in the properly localized t-livin's pro- necessarily the total lack of BIRC7 expression) were apoptotic functions. related to a better prognosis - possibly due to the pro- Point mutations to the RING domain resulted in proper peri-nuclear distribution and further Golgi
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 236
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
localization, but abrogated the pro-apoptotic effect (Sanna et al., 2002; Chen et al., 2010). Moreover, of t-livin. However, RING-mutated full-length BIRC7 may play a role in the WNT/ CTNNB1 BIRC7 was found in both nucleus and cytoplasm, (Wnt/β-catenin) signaling pathway, a key suggesting that RING domain, opposite to what was component of gene activation with outcomes on observed for the truncated forms, may affect the sub- tumor development through the activity of TCF (T- cellular localization of full-length BIRC7 (Nachmias cell factor) transcription factors (Uematsu et al., et al., 2007a). Moreover, while the occurrence of 2003). Indeed, Yuan and collaborators (2007) intact full-length BIRC7 in the cytoplasm directly confirmed BIRC7 to be a target of the β-catenin/TCF correlates with resistance to apoptosis, the presence complex, suggesting their transcriptional regulation of t-livin in the nucleus is associated with increased by upon BIRC7 (Yuan et al., 2007). Recent studies cellular apoptosis. have also demonstrated a role for BIRC7 in regulating the epithelial-mesenchymal transition in Function colorectal cancer cells, favoring metastasis by the Most IAPs are thought to directly interact with activation of the p38/ GSK3B pathway (Han et al., caspases and block their activity (Kasof & Gomes, 2017). 2001), and the integrity of the BIR domain is BIRC7 overexpression has been also associated with necessary to achieve this effect. In fact, BIRC7 has tumor aggressiveness, chemoresistance and reduced been initially proposed to bind and inhibit CASP9, sensitivity to radiation, while silencing of BIRC7 has but not CASP1, CASP2, CASP3, CASP6, CASP7 or been shown to lessen such features, both in vitro and CASP8 (Vucic et al., 2000; Vucic et al., 2002). in vivo. When SMMC-7721 cells were transfected However, subsequent work carried out by the same with BIRC7 siRNA, mRNA and protein levels of group demonstrated that BIRC7 established a both splice variants, BIRC7α and β, were greatly weaker interaction with caspases 3 and 9 when downregulated. Moreover, transfected cells compared to that of XIAP (Vucic et al., 2005) displayed G1-arrest and a diminished S-phase cell (Figure 2). Moreover, three critical BIR residues count, reduced invasiveness, and re-established a were found responsible for BIRC7's lower caspase response to apoptotic stimuli (Liu et al., 2010). inhibition potency - Ser150, Gln167 and Glu168 - BIRC7-silenced SCG-7901 cells, in turn, regained while XIAP's corresponding residues- Gly326, sensitivity to cytotoxic chemotherapy drugs, such as His343, and Leu344- rendered the latter IAP a 5-fluorouracil (5-FU) and cisplatin (Wang et al., stronger inhibitor. Once the critical residues were 2010). In xenograft models, HCT116 tumors treated replaced for those of XIAP, the mutant BIRC7 with BIRC7 siRNA presented reduced volume in a actually showed greater inhibition towards caspase 9 dose-dependent fashion, while mice maintained than native XIAP (Vucic et al. 2005). Nevertheless, healthy body weight and no signs of toxicity (Oh et BIRC7 was demonstrated to bind with high affinity al., 2011). Animal models were also used to to the pivotal pro-apoptotic, IAP-antagonizer demonstrate the differential effects of BIRC7 mitochondrial protein DIABLO (SMAC) through isoforms in tumorigenesis. BIRC7α was shown to the BIR domain, while BIR-mutations were shown promote tumor progression, whereas those to abolish BIRC7-SMAC/DIABLO interaction (Ma expressing BIRC7β inhibited tumor growth due to et al., 2006). In this scenario, the anti-apoptotic high degrees of cleavage, mediated by natural killer function played by BIRC7 is essentially revealed (NK) cells activity, of this variant into t-livin, which through the sequestration of SMAC/DIABLO, thus has a pro-apoptotic effect. Nevertheless, the abrogating the anti-IAP effect exerted by such expression of a mutated BIRC7β with lowered protein (Chai et al., 2000; Liu et al., 2007). inclination to undergo cleavage restored a positive Furthermore, Ma and colleagues (2006) showed that effect of tumor growth (Abd-Elrahman et al., 2009). BIRC7, in fact, resorts to the E3 ubiquitin ligase In turn, it was also established that, while BIRC7α function of the RING domain to target enhanced killing by NK cells, the β variant took on a SMAC/DIABLO for degradation through the modest protective effect against apoptosis induced ubiquitin-proteasome pathway. by NK cells, however, in Jurkat cells, this action BIRC7 has prompted apoptosis blockage induced by occurred alongside a concurrent inhibitory trigger, a number of death receptors, such as FAS, and not self-sufficiently. Nevertheless, when both TNFRSF1A (TNFR1), TNFRSF10A (DR4) and isoforms were detected in melanoma cells, a low TNFRSF10B (DR5) (Vucic et al., 2000), and has killing rate was observed (Nachimas et al., 2007b). been associated to other proteins that are within the The paradoxical pro-apoptotic effects of BIRC7, apoptotic pathway, thus inducing further indirect although baring intact BIR domains, are exerted by caspase inhibition. Similar to XIAP, the ability of the truncated forms of both variants; still, t-livin β BIRC7 to activate MAPK8 (JNK1), a protective was found to give a stronger, however less stable, pathway against apoptosis induced by TNF (TNF- pro-apoptotic effect than t-livin α. t-Livin occurs &alpha); and interleukin, was verified by the around the cell nucleus, although not sturdily bound MAP3K7 / TAB1 (TAK1/TAB1) signaling cascade to that, and accumulates in the Golgi apparatus.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 237
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
Resorting to mutagenesis and co-localization cells, when these were treated with a pan-caspase studies, Nachmias and colleagues further inhibitor, t-livin-induced cell death was only demonstrated that an intact RING domain and partially abrogated, implying an aptitude of t-livin to merely the first N-terminal glycine (G53) residue induce cell death in situations where the apoptotic were sufficiently responsible for t-livin's localization process is compromised (Shiloach et al., 2014). to Golgi apparatus and also for its pro-apoptotic function, while deletion of either of these regions Homology resulted in restoration of anti-apoptotic effect BIRC7 has a high homology among different species (Nachimas et al., 2007a). Additionally, t-livin has (Table 1). also been termed a flexible inducer of cell death once % Identity for: Homo Shiloach and colleagues (2014) recognized its Symbol Protein DNA sapiens BIRC7 capacity of inciting necrosis, like in 293T cells, or apoptosis, like in A549 and MelA1, and such vs. X. tropicalis birc7 55.4 58.2 distinction may be possibly linked to TP53 status. vs. D. rerio birc7 60.3 62.7 Moreover, once the BIR domain was deleted from t- vs. G. gallus BIRC7 55.4 58.2 livin, the prior necrotic effect observed in 293T cells was replaced by an apoptotic effect, regardless of its vs. D. rerio birc7 59.1 65.0 inactive TP53. Both effects, apoptosis and necrosis, vs. G. gallus BIRC7 60.3 62.7 were linked to activation of JNK pathway. vs. X. tropicalis birc7 59.1 65.0 However, once the BIR domain was deleted from t- Table 1. Comparative identity of human BIRC7 with other species (Source: http://www.ncbi.nlm.nih.gov/homologene) livin, 293T cells failed to express JNK, suggesting a role for BIR in activation of this pathway. In MelA1
Figure 2. Suggested mechanisms of action of BIRC7 on apoptosis regulation. BIRC7 (livin) acts on cytoplasm and nucleus and is involved different cellular functions: cell survival, epithelial mesenchymal transition and up-regulation of pro-survival genes. In cytoplasm, BIRC7 modulates apoptosis pathway by indirectly regulating caspases 3 and 7. BIRC7 may block SMAC/DIABLO, a factor released by mitochondria, which subsequently inhibit the BIRC4 (XIAP). Also, BIRC7 induces the phosphorylation of P38, inhibiting GSK3B. It also induces the phosphorylation of JNK, mediating the translocation of C-JUN to the nucleus that induces the transcription of genes involved in pro-survival such as AP-1.
Mutations
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 238
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
Somatic (estrogen receptor), or PGR (progesterone receptor) status. However, expression of BIRC7 is higher in Recurrent mutations in the BIRC7 gene are rare. breast cancers classified under histological grade III Among the 48,467 unique samples reported in when compared to grades I and II (88.9% vs. 46.9%). COSMIC (Catalogue of Somatic Mutations in Similarly, the positive expression rate of BIRC7 in Cancer; TNM in breast cancer stages III and IV (87.5%) was http://cancer.sanger.ac.uk/cancergenome/projects/c higher than in other stages (50%). In breast cancer osmic), only 99 presented BIRC7 mutations (71 cells, BIRC7 gene silencing induced G0/G1 cell missense substitutions, 26 synonymous cycle arrest. BIRC7 was highly expressed in high- substitutions, 2 nonsense substitutions, and 1 invasive breast cancer cells and promoted breast frameshift insertion). Similar findings are reported in cancer cell migration and invasion via the activation cBioPortal (http://www.cbioportal.org), in which, of AKT signaling and induction of epithelial- among the 10,967 cancer samples accessed, somatic mesenchymal transition (EMT) in vitro and in vivo mutations in BIRC7 were shown in merely 0.5% of (Li et al., 2012). the tested samples (corresponding to 59 mutations, EMT is a key step in tumor progression via the of which 54 are missense substitutions, 4 truncated induction of a highly invasive phenotype, and its genes, and 1 other mutation). BIRC7 gene has been molecular mechanisms have been extensively localized to the long arm of chromosome 20 on studied. The loss of epithelial markers such as CDH1 20q13.3, a region frequently amplified in melanomas (E-cadherin), and the gain of mesenchymal markers and other malignancies (Vucic et al., 2000; Ibrahim such as CDH2 (N-cadherin) and VIM (vimentin) are et al., 2014; Choi et al., 2019); the hallmarks of EMT. Overexpression of BIRC7 resulted in a similar loss of epithelial markers and a Implicated in gain of mesenchymal markers, suggesting that Ampullary carcinoma BIRC7 was actively involved in the EMT process in breast cancer cells. These results suggested that In ampullary carcinoma, BIRC7 was detected in BIRC7 participates of EMT by altering expression 46.5% of cases, in which its expression was found and activation of proteins involved in metastasis (Li predominantly in the cytoplasm, and only in 2.8% in et al., 2013b). the nucleus. High BIRC7 expression positively Together, these findings indicate that BIRC7 correlated with cell differentiation, tumor-node- promoted the progression and metastasis of breast metastasis (TNM) staging, and lymph node cancer through the regulation of EMT by activating metastasis. BIRC7 expression correlated negatively the p38/GSK3β pathway. A deeper understanding of with caspase 3 levels and positively with Ki-67 the role of BIRC7-induced EMT in breast cancer levels, demonstratinsg a decrease in apoptosis rate may provide effective targets for therapy, especially and an increase in cell proliferation in this cancer in triple-negative breast cancer (Han et al., 2017, Etti type. In addition, survival of patients with high et al., 2017). BIRC7 expression was shorter compared with that of patients with low BIRC7 expression (Xue et al., Central nervous system cancer 2013). BIRC7 overexpression was reported in cerebral Breast cancer neoplasms, including neuroblastomas, glioblastomas, and tumors derived from neural crest The investigation of BIRC7 gene expression in 8 cells. In most brain tumors, upregulation of BIRC7 breast cancer cell lines revealed that this gene was expression was associated with radio- and expressed in all cells assessed. At least 6 out of the 8 chemotherapeutics resistance (Dasgupta et al., breast cancer cell lines (BT549, MDA-MB-435, 2010). MDA-MB-231, MDA-MB-468, MCF-7, SK-BR-3 In neuroblastomas, 80% of cases presented high and ZR-75-30) showed relatively increased BIRC7 BIRC7 expression. Experimental findings indicate mRNA and protein expression compared to the non- that BIRC7 may play a role in drug-resistance in malignant breast cell line, HBL100. Moreover, neuroblastoma, particularly in aggressive and BIRC7 expression was found in higher levels in MYCN amplified tumors. These data strongly invasive breast cancer cells, when compared to non- support that therapeutic targeting of BIRC7 to block invasive ones (Fan et al., 2013, Crnkovic-Mertens et its antiapoptotic effect could be an interesting al., 2010). strategy for the treatment of this disease (Dasgupta Clinicopathological studies revealed that the et al., 2010). expression levels of BIRC7 in breast cancer tissues In glioblastoma multiforme, the tumor hypoxia- (62%) are higher than that of adjacent (35%) and induced BIRC7 expression may represent a pathway normal breast tissues (25%). Still, the expression of for resistance to radio- and chemotherapeutics, since BIRC7 in breast cancer is not closely related to age, experimental studies showed that siRNA directed menopause status, histological grade, ESR1
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 239
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
against BIRC7 inhibited tumor growth (Hsieh et al., chemoresistance (Ding et al., 2013). BIRC7 2014; Yuan et al., 2011). knockdown also improved the sensitivity of Cervical carcinoma colorectal cells to 5-FU (Liu et al., 2018). Colorectal cancer chemoresistance in HCT-8/V due to Cervical cancer is one of the common gynecologic overexpression of this protein has also been malignancies, and resistance to cisplatin is a concern attributed in response to vincristine (VCR), in the clinical practice. In functional studies using etoposide (VP-16), and 5-FU (Wang et al., 2010). the human cervical adenocarcinoma cell line, HeLa (which highly expresses BIRC7), inhibition of Esophageal carcinoma expression of BIRC7 by RNAi enhanced the activity BIRC7 expression was associated with tumor of caspase 3, reduced BCL2 expression, and staging and progression in human esophageal increased BAX, further inducing apoptosis and carcinoma. Moreover, a positive correlation with improving the effects of cisplatin (Yu Wang, 2009). VEGFA expression has also been demonstrated in Colorectal cancer these tumor types (Chen et al., 2008). BIRC7 expression was detected in 54.1% of patients Gastric cancer with colorectal cancer, specifically on the base of BIRC7 expression was found in 52.5% of gastric colorectal crypts in adenoma and throughout the cancer samples, compared to 6.7% in that of adjacent epithelium in carcinoma, while such protein was not normal gastric tissues (Liang et al., 2012). Similar detected in normal colorectal mucosa (Xi et al., results were described by Ou et al. (2014), who 2011), (Wang et al., 2014). A high BIRC7 revealed that BIRC7 expression was elevated in expression rate was negatively associated to overall tumors (64.1%) when compared to adjacent non- survival, but showed no correlation with age, gender, cancer tissues (30.8%) obtained from patients with degrees of differentiation, and TNM staging in this gastric cancer. Both studies found a positive malignancy (Xi et al., 2011; Myung et al, 2013). correlation of BIRC7 expression with tumor In primary tumors, BIRC7 expression was differentiation and lymph node metastasis. significantly increased compared with adjacent or Furthermore, Ou et al. (2014) demonstrated that distant normal mucosa, in which expression was BIRC7 depletion inhibited cell proliferation and independently related to survival outcomes in invasion and induced apoptosis - showed by patients with rectal cancer (Ding et al., 2013). In decreased expression of p38 MAPK, VEGF, and addition, BIRC7 was related to pathological grade, MMP2 and increased expression of caspase 3 in extent of invasion and amount of lymph node vitro. This feature also induced cell cycle arrest, with metastasis, contributing to poor prognosis of mid- a decrease of cyclin D1 and CDK4 and CDK6, and distal rectal cancer following surgery (Su et al., an increase in expression of CDKN1A (p21) and 2017). CDKN1B (p27) (Chung et al., 2013). Comparably, Overexpression of BIRC7 induced proliferation, in vivo assessments proved tumor size had decreased migration, and invasion of cancer colorectal cells, after treatment with siRNA (Oh et al., 2011) or which was reverted by BIRC7 depletion. Moreover, shRNA (Ou et al., 2014) targeting BIRC7. this overexpression promoted EMT, as evidenced by Head and neck squamous cell a decrease in E-cadherin expression and an increase in mesenchymal markers, including vimentin, carcinoma SNAI2 (SLUG), and SNAI1 (SNAIL) (Ge et al., Yoon et al. (2017) demonstrated that BIRC7 is 2016). Additionally, knockdown of BIRC7 involved in chemoresistance in head and neck promoted cell cycle arrest by decreasing CCND1 36 squamous cell carcinoma (HNSCC). This was and CCND3 (cyclins D1 and D3), CDK4 and CDK6, evidenced in experiments using human HNSCC cell and by inducing CDKN1B (p27) expression. lines, where depletion of BIRC7 enhanced Moreover, MAPK signaling cascades were cytotoxicity of cisplatin, 5-FU, and docetaxel. significantly blocked by knockdown of BIRC7 Additionally, the authors detected elevated (Myung et al, 2013), while BIRC7 silencing using expression of cleaved caspases-3 and -7 and PARP1, siRNA also decreased cell proliferation and when compared with control cells, after clonogenicity and increased apoptosis rates (Zou et chemotherapy treatment, suggesting that reduction al., 2014). of BIRC7 levels is associated to sensitization to In colorectal cancer cell lines, BIRC7 expression apoptosis (Yoon et al., 2017). was attributed to cisplatin resistance. BIRC7 mRNA Kidney cancer levels was upregulated after cisplatin treatment in a dose- dependent manner. According to Xu et al. (2010), overexpression of By contrast, knockdown of BIRC7 by siRNA BIRC7 was detected in 40.7% of the cases of renal rendered colon cancer cells more sensitive to cell carcinoma (RCC). Similarly, studies carried out cisplatin, reinforcing its involvement in by Zang et al. (2013) revealed BIRC7 was detected in 44% of cases of RCC. Furthermore, when
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 240
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
metastatic lymph nodes were detected, cases with leukemia that further lead to leukemogenesis overexpression of BIRC7 came up to 59% (Wagener (Ibrahim et al., 2014; Choi et al., 2019). et al., 2007). Overexpression of BIRC7 protein in newly Clinical studies indicated that tissues from advanced diagnosed children with acute leukemia suggested an stages of RCC have greater expression of BIRC7 important role for this protein in carcinogenesis and (Wang et al., 2016). Functional studies strongly progression of such disease (Lv et al., 2015). Yang suggested that BIRC7 is a bridge for apoptosis and et al. (2010) also suggested that the expression of autophagy. Silencing of BIRC7 induced apoptosis BIRC7α and BIRC7β may be associated with and autophagic cell death while also increasing genesis and development of acute leukemia in sensitivity to cisplatin in RCC cells (Wang et al., childhood, and that this could be used as a molecular 2016). marker of childhood acute leukemia. In addition, Laryngeal cancer BIRC7 can be used as a new target for leukemia treatment, as RNAi technology effectively inhibited Studies have reported that BIRC7 inhibits cell expression of BIRC7 (Yang et al., 2010; Yan et al., apoptosis via modulation of caspase 3, caspase 7 and 2011; Ibrahim et al., 2014). PARP1 in human larynx and pharynx carcinoma cells. In laryngohypopharyngeal carcinoma Liver cancer (LHSCC), BIRC7 expression was predominantly BIRC7 mRNAs were significantly increased in identified in tumors (36.7%) when compared to the samples from hepatocellular carcinoma patients adjacent healthy mucosa. Additionally, induction of compared to their normal hepatic tissues (Augello et apoptosis by BIRC7 knockdown occurred through al., 2009), hepatitis, and hepatic cirrhosis tissues activation of caspases-3 and 7 and PARP1. Such data (Guo et al., 2013). indicate that BIRC7 induces tumorigenic activities in BIRC7 inhibition, by shRNA, promoted apoptosis in LHSCC, such as resistance to apoptosis. Thus, hepatocellular carcinoma cell line HepG2, which BIRC7 silencing may be useful for therapeutic was even more evident with a combinatory strategy intervention against tumor progression in LHSCC using the co-transfection with a shRNA targeting (Kuang et al., 2017, Liu et al., 2016). BIRC5 (Xu et al., 2014). Additionally, another study In patients with nasopharyngeal carcinoma (NPC), demonstrated that inhibition of BIRC7 using shRNA high expression levels of BIRC7 occurred in 65.1% increased chemosensitivity of HepG2 cells (Liu et of cases, suggesting BIRC7 to be implicated in al., 2015). progression of such disease. Thus, this may be a Similar results were obtained in other hepatocellular useful prognostic biomarker for NPC (Kuang et al., carcinoma cell line, SMMC-7721, using BIRC7 2017, Liu et al., 2016). Nevertheless, observational siRNA. Inhibition of BIRC7 sensitized cells to pro- studies have shown that the efficacy of radiotherapy apoptotic stimuli associated with caspase 3 is greater in patients who did not express BIRC7 activation and, moreover, promoted cell growth compared to those with BIRC7 overexpression, inhibition specifically by mitotic arrest. In addition, indicating that BIRC7 may be associated with a poor BIRC7 depletion reduced the invasive capacity of prognosis for NPC and LHSCC (Kuang et al., 2017, hepatocellular carcinoma cells, demonstrating that Liu et al., 2016). BIRC7 is not only involved in resistance to Leukemia apoptosis, but also in cell proliferation and invasiveness (Liu et al., 2010). Overexpression of BIRC7 was found in BIRC7 not only provided resistance to approximately 81% of patients with acute myeloid hepatocellular carcinoma cells, but also significantly leukemia (AML), and a positive correlation between contributed to cell proliferation and invasion (Liu, the expression of BIRC7 and high white blood cell 2010). In addition, clinical studies showed that counts was reported (Zareifar et al., 2018). In AML, overexpression of BIRC7α isoform correlates with a genetic aberrations were found to activate BIRC7- high risk of relapse in liver cancer (Liu, 2007; Liu, related signal transduction pathways, resulting in 2010). greater proliferation and/or survival of leukemia Inhibition of BIRC7 gene expression was associated progenitor cells by affecting transcription factors or with a strong increase in apoptotic response in the transcription coactivation components, resulting in presence of pro-apoptotic agents, indicating that differentiated blocking and/or aberrant acquisition of BIRC7 depletion led to sensitization to apoptotic self-renewal properties by hematopoietic progenitor stimuli (Mazumder, 2008; Liu, 2010). Moreover, cells (Dohner et al., 2008; Hanahan et al., 2000; negative regulation of BIRC7 expression induced Zareifar et al., 2018). cell cycle arrest at the G0/G1 phase, indicating that Additionally, levels of BIRC7 expression in acute BIRC7 modulation may be a potential targeted lymphoblastic leukemia (ALL) were also shown to approach for the treatment of liver cancer (Wang, be elevated. Such feature may be attributed to the 2008; Liu, 2010) different mutations that occurred in the two types of
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 241
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
Lung cancer proliferation of LiBr melanoma cells (Wang et al., 2007).DISEASE High levels of BIRC7 were detected in approximately 61.5% of cases of non-small cell lung Mesothelioma cancer (NSCLC). Conversely, BIRC7 BIRC7 protein was expressed in 18% of malignant overexpression was associated with poor prognosis pleural mesothelioma (MPM) and was usually found and lymph node metastasis (Crnkovic-Mertens et al., in the nucleus of these cells. Only BIRC2 (IAP1) and 2006; Yuan et al., 2008). BIRC7 proteins were expressed in the nucleus of Functional studies showed that silencing of BIRC7 MPM tumors (Gordon et al., 2007). increased the efficiency of chemotherapy or radiotherapy in pulmonary adenocarcinomas. In Oral squamous cell carcinoma addition, this protein is portrayed as a potential BIRC7 was increased in human oral squamous cell predictive biomarker for the prognosis of lung carcinoma (OSCC) tissues compared with the adenocarcinoma besides a promising strategy for adjoining healthy mucosa. Additionally, BIRC7 drug-resistant lung adenocarcinoma (Yang et al., knockdown reduced cell invasion, migration, and 2014; Wu et al., 2016; Liang et al., 2017). proliferation in the human OSCC cells, while also Lymphoma promoting apoptosis, evidenced by activation of caspases (Lee et al., 2014). The expression of BIRC7 in non-Hodgkins lymphoma (NHL) was significantly higher than in Ovarian cancer lymph node samples in classical Hodgkins Elevated expression levels of BIRC7 isoforms were lymphomas (CHL). This difference in BIRC7 detected in human epithelial ovarian cancer (EOC) expression was also observed when comparing two in comparison to benign ovarian neoplasms. NHL subtypes - large B-cell lymphoma (DLBCL) Moreover, depletion of BIRC7 levels by shRNA and large cell anaplastic lymphoma for CHL - where result in profound pro-apoptotic and antiproliferative a significantly higher expression of BIRC7 occurred effects, and was associated with the activation of in DLBCL (Tanhaei et al., 2014; Ziaei et al, 2015; caspase signaling, increased apoptosis and recovered Browne et al., 2003). sensitivity to chemotherapy drugs (Liu et al., 2012). BIRC7 plays a critical role in the pathogenesis of lymphomas and was detected in 40% of cases Osteosarcoma Hodgkin's lymphoma and 48% in cases of Burkitt's BIRC7 expression was upregulated in 58.7% of lymphoma, indicating that BIRC7 could be a human osteosarcoma tissue, which, in turn, showed potential marker and therapeutic target for these a significant correlation with microvascular density, diseases (Abd-Elrahamn et al., 2009; Kalungi et al., suggesting that regulation of BIRC7 expression 2012). could further control the physiological repair of Melanoma pathological angiogenesis in osteosarcomas (Li et al, 2014; Guan, 2015) BIRC7 is also named Melanoma-Inhibitor Apoptosis As BIRC7 has rarely been found in osteochondroma Protein (ML-IAP) due to the first paper that reported tissues, this feature may be indicative of a specificity an elevated expression of this IAP in melanoma cell of such protein to osteosarcomas. In invasive lines, when compared to that of some lymphomas, osteosarcomas metastatic tissues, BIRC7 was fetal kidney, fetal liver, testis and thymus. The study notoriously elevated, suggesting that the higher further demonstrated that BIRC7 mRNA was highly levels of this protein conferred anti-apoptotic effects expressed in melanoma cell lines but not in normal and endurance of these tumor cells (Li et al, 2012). human melanocytes. Moreover, such expression was In this context, BIRC7 may serve as a promising consistent with a resistant phenotype to therapeutic target for the treatment of chemotherapeutic agents, also becoming the first osteosarcomas. Furthermore, expression of BIRC7 work to demonstrate the importance of BIRC7 on was related to a poor prognosis of osteosarcoma and chemoresistance (Vucic et al., 2000). its detection may play an important role in evaluation BIRC7 showed low occurrence in nevi (15%), of this type of cancer (Li et al, 2012; Li et al, 2014; however an increased expression in melanoma (47.6 Sun et al., 2018). - 70.7%), in which these levels came up to 95% in metastatic melanoma, suggesting this protein to be Pancreas cancer involved in melanoma progression (Hartman Czyz, BIRC7 was shown to be overexpressed in 25% of 2013). In this scenario, high BIRC7 levels were pancreatic cancer cases. Additionally, this protein associated with a poor prognosis in melanoma displayed strong reactivity in tumor tissues by in situ (Lazar et al., 2012). Still, silencing of BIRC7 hybridization studies. Such reactivity was not found induced apoptosis, by activation of caspase 3, and in all ducts, indicating heterogeneity for BIRC7 cell cycle arrest at the G0/G1 phase, thus inhibiting expression is not merely related to tumor type or
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 242
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
origin, but also in different areas of a same tumor ODN) was evaluated in combination with 5-FU in (Lopes et al., 2007, Liu et al., 2011). the hepatocellular carcinoma cell line HepG2 and In PANC-1 cells, pharmacological studies have verified that such treatment decreased cell viability, shown oxymatrine-induced apoptosis to be related to increased apoptosis and induced cell cycle arrest at downregulation of BIRC7 and upregulation of the the S phase when compared with CpG-ODN or 5-FU BAX / BCL2 ratio (Lopes et al., 2007, Liu et al., alone. Alongside, expression of mRNA for BIRC7 2011). decreased in cells treated with CpG-ODN alone or in Prostate cancer combination with 5-FU, but increased in cells treated with 5-FU alone (Liang et al., 2013). Expression of BIRC7β was detected in 51.9% of Supplementation diets rich in n-3 polyunsaturated cases of testicular germ cell tumor, whereas 28.2% fatty acids (PUFAs) have been associated with a of cases of such pathology expressed BIRC7α reduced risk for several types of cancer which, in (Kempkensteffen et al., 2008). turn, has been linked to their effect in reducing the In prostate carcinoma tissues, BIRC7 overexpression levels of expression of IAP family members was associated with high-grade clinical stages of the associated with chemotherapy resistance and cancer disease and metastasis. This protein plays an malignancy, such as BIRC7 and BIRC5 (Slagsvold important role in initiation of prostate cancer and et al., 2010). promotes cell proliferation by regulating the G1/S Funding: Process numbers: 2017/09022-8, cell cycle transition. BIRC7 has been related with 2018/06522-2 and 2015/17177-6, Fundação de invasion of cancer cells in the surrounding prostate Amparo à Pesquisa do Estado de São Paulo tissue by affecting NF-KB signaling pathway and (FAPESP) and Coordenação de Aperfeiçoamento de expressions of FN1 and CXCR4, resulting in Pessoal de Nível Superior (CAPES). inhibition of PTK2 (FAK) and SRC, and of ITGA5 and ITGB3 (integrins a5 and b3) (Ye et al, 2011; References Chen et al., 2012) Abd-Elrahman I, Hershko K, Neuman T, Nachmias B, Retinocytoma Perlman R, Ben-Yehuda D. The inhibitor of apoptosis BIRC7 was found to be upregulated in retinocytoma protein Livin (ML-IAP) plays a dual role in tumorigenicity. Cancer Res. 2009 Jul 1;69(13):5475-80 compared to the normal control group. Treatment with topotecan induced apoptosis through the Altucci P, Abbate GF, Alagia I, Leonessa V. Clinical evaluation of tobramycin in respiratory and systemic inhibition of BIRC7 expression (Zhang et al., 2013). infections in immunodepressed and normal patients. J Urinary tract cancer Infect Dis. 1976 Aug;134 Suppl:S182-6 BIRC7 expression was upregulated in urinary tract Ambrosini G, Adida C, Sirugo G, Altieri DC. Induction of apoptosis and inhibition of cell proliferation by survivin gene cancers - bladder transitional cell carcinoma (TCC) targeting. J Biol Chem. 1998 May 1;273(18):11177-82 and bladder squamous cell carcinoma (SCC) -when paralleled with corresponding adjacent non- Ashhab Y, Alian A, Polliack A, Panet A, Ben Yehuda D. Two splicing variants of a new inhibitor of apoptosis gene with neoplastic tissues. Such elevated expression was different biological properties and tissue distribution pattern. significantly associated with higher tumor grades FEBS Lett. 2001 Apr 20;495(1-2):56-60 and staging, suggesting BIRC7 contributes to the Augello C, Caruso L, Maggioni M, Donadon M, Montorsi M, progression of bladder carcinoma (Gayyeda Santambrogio R, Torzilli G, Vaira V, Pellegrini C, Roncalli Tawfiekb, 2015). M, Coggi G, Bosari S. Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in To be noted hepatocellular carcinoma. BMC Cancer. 2009 Apr 27;9:125 Browne P, Petrosyan K, Hernandez A, Chan JA. The B-cell Pharmacological advances targeting BIRC7 in transcription factors BSAP, Oct-2, and BOB.1 and the pan- cancer: B-cell markers CD20, CD22, and CD79a are useful in the Treatment with siRNA targeting BIRC7 differential diagnosis of classic Hodgkin lymphoma. Am significantly suppressed cancer cell growth and J Clin Pathol. 2003 Nov;120(5):767-77 enhanced cytotoxicity of typical anticancer drugs Budhidarmo R, Day CL. IAPs: Modular regulators of cell such as 5-FU and oxaliplatin (L-OHP) in colorectal signalling. Semin Cell Dev Biol. 2015 Mar;39:80-90 cancer, demonstrating such protein to be a relevant Chen F, Yang D, Wang S, Che X, Wang J, Li X, Zhang Z, target in oncology (Oh et al., 2016). Similarly, a Chen X, Song X. Livin regulates prostate cancer cell study using a protamine single-chain antibody fusion invasion by impacting the NF-κB signaling pathway and the protein (anti-MM scFv-tP) to deliver BIRC7 siRNA expression of FN and CXCR4. IUBMB Life. 2012 to melanoma LiBr cells revealed suppression of cell Mar;64(3):274-83 proliferation and induction of apoptosis, both in vitro Chen J, Xie F, Zhang L, Jiang WG. iASPP is over- and in vivo (Wang et al., 2017). expressed in human non-small cell lung cancer and regulates the proliferation of lung cancer cells through a p53 A synthetic oligonucleotide containing associated pathway BMC Cancer 2010 Dec 30;10:694 unmethylated CpG oligodeoxynucleotides (CpG-
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 243
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
Chen L, Ren GS, Li F, Sun SQ. Expression of livin and M. Fascin is involved in the chemotherapeutic resistance of vascular endothelial growth factor in different clinical stages breast cancer cells predominantly via the PI3K/Akt pathway of human esophageal carcinoma World J Gastroenterol Br J Cancer 2014 Oct 14;111(8):1552-61 2008 Oct 7;14(37):5749-54 Gong J, Chen N, Zhou Q, Yang B, Wang Y, Wang X. Chen N, Gong J, Chen X, Meng W, Huang Y, Zhao F, Wang Melanoma inhibitor of apoptosis protein is expressed L, Zhou Q. Caspases and inhibitor of apoptosis proteins in differentially in melanoma and melanocytic naevus, but cutaneous and mucosal melanoma: expression profile and similarly in primary and metastatic melanomas J Clin Pathol clinicopathologic significance Hum Pathol 2009 2005 Oct;58(10):1081-5 Jul;40(7):950-6 Gordon GJ, Mani M, Mukhopadhyay L, Dong L, Edenfield Cheng T, Zhang JG, Cheng YH, Gao ZW, Ren XQ. HR, Glickman JN, Yeap BY, Sugarbaker DJ, Bueno R. Relationship between PTEN and Livin expression and Expression patterns of inhibitor of apoptosis proteins in malignancy of renal cell carcinomas Asian Pac J Cancer malignant pleural mesothelioma J Pathol 2007 Prev 2012;13(6):2681-5 Mar;211(4):447-54 Choi J, Hwang YK, Sung KW, Lee SH, Yoo KH, Jung HL, Guan HP, Sun JZ, Feng XL, Chen JS, Chen FJ, Cheng XF, Koo HH, Kim HJ, Kang HJ, Shin HY, Ahn HS. Expression of Liu XW, Ni B. Effects of RNA interference-mediated Livin, an antiapoptotic protein, is an independent favorable knockdown of livin and survivin using prognostic factor in childhood acute lymphoblastic leukemia monomethoxypolyethylene glycol-chitosan nanoparticles in Blood 2007 Jan 15;109(2):471-7 MG-63 osteosarcoma cells Mol Med Rep 2016 Feb;13(2):1821-6 Chung CY, Park YL, Kim N, Park HC, Park HB, Myung DS, Kim JS, Cho SB, Lee WS, Joo YE. Expression and Guo H, Gao YT, Zhang Q, Jing L, Liu T, Shi WX, Zhai DK, prognostic significance of Livin in gastric cancer Oncol Rep Jing X, Du Z. Expression and clinical significance of livin 2013 Nov;30(5):2520-8 protein in hepatocellular carcinoma Dis Markers 2013;35(5):489-96 Crnković-Mertens I, Bulkescher J, Mensger C, Hoppe-Seyler F, Hoppe-Seyler K. Isolation of peptides Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors to blocking the function of anti-apoptotic Livin protein Cell Mol modulators of NF-kappaB, inflammation and cancer Nat Life Sci 2010 Jun;67(11):1895-905 Rev Cancer 2010 Aug;10(8):561-74 Döhner K, Döhner H. Molecular characterization of acute Han Y, Zhang L, Wang W, Li J, Song M. Livin promotes the myeloid leukemia Haematologica 2008 Jul;93(7):976-82 progression and metastasis of breast cancer through the regulation of epithelialmesenchymal transition via the Dasgupta A, Alvarado CS, Xu Z, Findley HW. Expression p38/GSK3β pathway Oncol Rep 2017 Dec;38(6):3574- and functional role of inhibitor-of-apoptosis protein livin 3582 (BIRC7) in neuroblastoma Biochem Biophys Res Commun 2010 Sep 10;400(1):53-9 Hanahan D, Weinberg RA. The hallmarks of cancer Cell 2000 Jan 7;100(1):57-70 Ding ZY, Liu GH, Olsson B, Sun XF. Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance Hariu H, Hirohashi Y, Torigoe T, Asanuma H, Hariu M, in colon cancer cells Tumour Biol 2013 Apr;34(2):683-93 Tamura Y, Aketa K, Nabeta C, Nakanishi K, Kamiguchi K, Mano Y, Kitamura H, Kobayashi J, Tsukahara T, Shijubo N, Ding ZY, Zhang H, Adell G, Olsson B, Sun XF. Livin Sato N. Aberrant expression and potency as a cancer expression is an independent factor in rectal cancer patients immunotherapy target of inhibitor of apoptosis protein with or without preoperative radiotherapy Radiat Oncol family, Livin/ML-IAP in lung cancer Clin Cancer Res 2005 2013 Dec 2;8:281 Feb 1;11(3):1000-9 El-Mesallamy HO, Hegab HM, Kamal AM. Expression of Hartman ML, Czyz M. Anti-apoptotic proteins on guard of inhibitor of apoptosis protein (IAP) livin/BIRC7 in acute melanoma cell survival Cancer Lett 2013 Apr 30;331(1):24- leukemia in adults: correlation with prognostic factors and 34 outcome Leuk Res 2011 Dec;35(12):1616-22 Hinds MG, Norton RS, Vaux DL, Day CL. Solution structure Etti IC, Abdullah R, Kadir A, Hashim NM, Yeap SK, Imam of a baculoviral inhibitor of apoptosis (IAP) repeat Nat Struct MU, Ramli F, Malami I, Lam KL, Etti U, Waziri P, Rahman Biol 1999 Jul;6(7):648-51 M. The molecular mechanism of the anticancer effect of Artonin E in MDA-MB 231 triple negative breast cancer cells Hsieh CH, Lin YJ, Wu CP, Lee HT, Shyu WC, Wang CC. PLoS One 2017 Aug 3;12(8):e0182357 Livin contributes to tumor hypoxia-induced resistance to cytotoxic therapies in glioblastoma multiforme Clin Cancer Gayyed MF, Tawfiek ER. Utility of SOX2 and Livin Co- Res 2015 Jan 15;21(2):460-70 Expression in the Prognosis of Bladder Cancer With Bilharzial and Non-Bilharzial Bladder Status World J Oncol Hu Y, Cherton-Horvat G, Dragowska V, Baird S, Korneluk 2015 Oct;6(5):446-455 RG, Durkin JP, Mayer LD, LaCasse EC. Antisense oligonucleotides targeting XIAP induce apoptosis and Gazzaniga P, Gradilone A, Giuliani L, Gandini O, Silvestri I, enhance chemotherapeutic activity against human lung Nofroni I, Saccani G, Frati L, Aglianò AM. Expression and cancer cells in vitro and in vivo Clin Cancer Res 2003 prognostic significance of LIVIN, SURVIVIN and other Jul;9(7):2826-36 apoptosis-related genes in the progression of superficial bladder cancer Ann Oncol 2003 Jan;14(1):85-90 Ibrahim L, Aladle D, Mansour A, Hammad A, Al Wakeel AA, Abd El-Hameed SA. Expression and prognostic significance Ge Y, Cao X, Wang D, Sun W, Sun H, Han B, Cui J, Liu B. of livin/BIRC7 in childhood acute lymphoblastic leukemia Overexpression of Livin promotes migration and invasion of Med Oncol 2014 May;31(5):941 colorectal cancer cells by induction of epithelial- mesenchymal transition via NF-κB activation Onco Targets Kalungi S, Wabinga H, Bostad L. Expression of apoptosis Ther 2016 Feb 29;9:1011-21 associated proteins Survivin, Livin and Thrombospondin-1 in Burkitt lymphoma APMIS 2013 Mar;121(3):239-45 Ghebeh H, Al-Khaldi S, Olabi S, Al-Dhfyan A, Al-Mohanna F, Barnawi R, Tulbah A, Al-Tweigeri T, Ajarim D, Al-Alwan
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 244
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
Kasof GM, Gomes BC. Livin, a novel inhibitor of apoptosis families, and releasing of cytochrome c J Exp Clin Cancer protein family member J Biol Chem 2001 Feb Res 2011 Jun 29;30:66 2;276(5):3238-46 Liu AH, He AB, Tong WX, Peng XL, Tian Q, Wang H, Li XG, Kempkensteffen C, Hinz S, Krause H, Jager T, Köllermann Xu HL. Prognostic significance of Livin expression in J, Weikert S, Christoph F, Schostak M, Miller K, Schrader nasopharyngeal carcinoma after radiotherapy Cancer M. Expression of splicing variants of the inhibitor of Radiother 2016 Jul;20(5):384-90 apoptosis livin in testicular germ cell tumors Tumour Biol 2008;29(2):76-82 Liu B, Han M, Wen JK, Wang L. Livin/ML-IAP as a new target for cancer treatment Cancer Lett 2007 Jun Kim DK, Alvarado CS, Abramowsky CR, Gu L, Zhou M, Soe 8;250(2):168-76 MM, Sullivan K, George B, Schemankewitz E, Findley HW. Expression of inhibitor-of-apoptosis protein (IAP) livin by Liu F, Chang H, Xu W, Zhai Y. The effects of Livin shRNA neuroblastoma cells: correlation with prognostic factors and on the response to cisplatin in HepG2 cells Oncol Lett 2015 outcome Pediatr Dev Pathol 2005 Nov-Dec;8(6):621-9 Nov;10(5):2957-2961 Kim SA, Yoon TM, Lee DH, Lee JK, Park YL, Chung IJ, Joo Liu H, Wang S, Sun H, Pan Z, Zhou W, Wu M. Inhibition of YE, Lim SC. Livin enhances tumorigenesis by regulating the tumorigenesis and invasion of hepatocellular carcinoma by mitogen-activated protein kinase signaling pathway in siRNA-mediated silencing of the livin gene Mol Med Rep human hypopharyngeal squamous cell carcinoma Mol Med 2010 Nov-Dec;3(6):903-7 Rep 2016 Jul;14(1):515-20 Liu S, Li X, Li Q, Liu H, Shi Y, Zhuo H, Li C, Zhu H. Silencing Kuang CM, Fu X, Hua YJ, Shuai WD, Ye ZH, Li Y, Peng Livin improved the sensitivity of colon cancer cells to 5- QH, Li YZ, Chen S, Qian CN, Huang W, Liu RY. BST2 fluorouracil by regulating crosstalk between apoptosis and confers cisplatin resistance via NF-κB signaling in autophagy Oncol Lett 2018 May;15(5):7707-7715 nasopharyngeal cancer Cell Death Dis 2017 Jun Liu X, Wang A, Gao H, Yuan Z, Jiao Y. Expression and role 15;8(6):e2874 of the inhibitor of apoptosis protein livin in chemotherapy Lazar I, Perlman R, Lotem M, Peretz T, Ben-Yehuda D, sensitivity of ovarian carcinoma Int J Oncol 2012 Kadouri L. The clinical effect of the inhibitor of apopotosis Sep;41(3):1021-8 protein livin in melanoma Oncology 2012;82(4):197-204 Liu Y, Guo Q, Zhang H, Li GH, Feng S, Yu XZ, Kong LS, Lee DH, Yoon TM, Kim SA, Park YL, Lee KH, Lim SC, Lee Zhao L, Jin F. Effect of siRNA-Livin on drug resistance to JK, Jo YE. Relationship between expression of Livin and the chemotherapy in glioma U251 cells and CD133(+) stem biological behavior of human oral squamous cell carcinoma cells Exp Ther Med 2015 Oct;10(4):1317-1323 Oncol Rep 2014 Dec;32(6):2453-60 Lopes RB, Gangeswaran R, McNeish IA, Wang Y, Lemoine Li CJ, Cong Y, Liu XZ, Zhou X, Shi X, Wu SJ, Zhou GX, Lu NR. Expression of the IAP protein family is dysregulated in M. Research progress on the livin gene and osteosarcomas pancreatic cancer cells and is important for resistance to Asian Pac J Cancer Prev 2014;15(20):8577-9 chemotherapy Int J Cancer 2007 Jun 1;120(11):2344-52 Li F, Yin X, Luo X, Li HY, Su X, Wang XY, Chen L, Zheng Lopez J, Meier P. To fight or die - inhibitor of apoptosis K, Ren GS. Livin promotes progression of breast cancer proteins at the crossroad of innate immunity and death Curr through induction of epithelial-mesenchymal transition and Opin Cell Biol 2010 Dec;22(6):872-81 activation of AKT signaling Cell Signal 2013 Lv J, Qin ZP, Zheng MF, Chen ZC, Wang Z. In vitro Jun;25(6):1413-22 application of RNA interference to silence livin gene Li X, Fan S, Li L, Wang L, Fan G, Zhao Q, Li Y. RNA expression to induce apoptosis in leukemia cells Eur Rev interference-mediated knockdown of Livin suppresses cell Med Pharmacol Sci 2015 Nov;19(22):4390-6 proliferation and invasion and enhances the Ma L, Huang Y, Song Z, Feng S, Tian X, Du W, Qiu X, chemosensitivity to cisplatin in human osteosarcoma cells Heese K, Wu M. Livin promotes Smac/DIABLO degradation Int J Oncol 2013 Jul;43(1):159-68 by ubiquitin-proteasome pathway Cell Death Differ 2006 Li Y, Li X, Fan G, Fukushi J, Matsumoto Y, Iwamoto Y, Zhu Dec;13(12):2079-88 Y. Impairment of p53 acetylation by EWS-Fli1 chimeric Machizaud F, Ounadjela K, Suran G. Magnetic and protein in Ewing family tumors Cancer Lett 2012 Jul structural properties of amorphous CoTi soft ferromagnetic 1;320(1):14-22 thin films II Structural properties Liang SR, Hu GR, Fang LJ, Huang SJ, Li JS, Zhao MY, Mazumder S, Plesca D, Almasan A. Caspase-3 activation Meng MJ. CpG oligodeoxynucleotides enhance is a critical determinant of genotoxic stress-induced chemosensitivity of 5-fluorouracil in HepG2 human apoptosis Methods Mol Biol 2008;414:13-21 hepatoma cells via downregulation of the antiapoptotic factors survivin and livin Cancer Cell Int 2013 Oct Myung DS, Park YL, Chung CY, Park HC, Kim JS, Cho SB, 26;13(1):106 Lee WS, Lee KH, Lee JH, Joo YE. Expression of Livin in colorectal cancer and its relationship to tumor cell behavior Liang Y, Wang H, Sun Y, Chen S, Wang H, Huang R, Zhao and prognosis PLoS One 2013 Sep 2;8(9):e73262 X, Fu W, Yang C. miR-198-induced upregulation of Livin may be associated with the prognosis and contribute to the Nachmias B, Mizrahi S, Elmalech M, Lazar I, Ashhab Y, oncogenesis of lung adenocarcinoma Oncol Rep 2017 Gazit R, Markel G, Ben-Yehuda D, Mandelboim O. Oct;38(4):2096-2104 Manipulation of NK cytotoxicity by the IAP family member Livin Eur J Immunol 2007 Dec;37(12):3467-76 Liang YZ, Fang TY, Xu HG, Zhuo ZQ. Expression of CD44v6 and Livin in gastric cancer tissue Chin Med J (Engl) Oh BY, Kim KH, Chung SS, Lee RA. Silencing the livin gene 2012 Sep;125(17):3161-5 enhances the cytotoxic effects of anticancer drugs on colon cancer cells Ann Surg Treat Res 2016 Dec;91(6):273-277 Ling Q, Xu X, Wei X, Wang W, Zhou B, Wang B, Zheng S. Oxymatrine induces human pancreatic cancer PANC-1 cells apoptosis via regulating expression of Bcl-2 and IAP
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 245
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
Oh BY, Lee RA, Kim KH. siRNA targeting Livin decreases Wagener N, Crnković-Mertens I, Vetter C, Macher- tumor in a xenograft model for colon cancer World J Göppinger S, Bedke J, Gröne EF, Zentgraf H, Pritsch M, Gastroenterol 2011 May 28;17(20):2563-71 Hoppe-Seyler K, Buse S, Haferkamp A, Autschbach F, Hohenfellner M, Hoppe-Seyler F. Expression of inhibitor of Ou JM, Ye B, Qiu MK, Dai YX, Dong Q, Shen J, Dong P, apoptosis protein Livin in renal cell carcinoma and non- Wang XF, Liu YB, Quan ZW, Fei ZW. Knockdown of Livin tumorous adult kidney Br J Cancer 2007 Nov 5;97(9):1271- inhibits growth and invasion of gastric cancer cells through 6 blockade of the MAPK pathway in vitro and in vivo Int J Oncol 2014 Jan;44(1):276-84 Wang H, Tan SS, Wang XY, Liu DH, Yu CS, Bai ZL, He DL, Zhao J. Silencing livin gene by siRNA leads to apoptosis Owens TW, Gilmore AP, Streuli CH, Foster FM. Inhibitor of induction, cell cycle arrest, and proliferation inhibition in Apoptosis Proteins: Promising Targets for Cancer Therapy malignant melanoma LiBr cells Acta Pharmacol Sin 2007 J Carcinog Mutagen 2013 May 27;Suppl 14 Dec;28(12):1968-74 Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in Wang H, Yang Y, Wang W, Guan B, Xun M, Zhang H, Wang cancer progression and therapy Integr Biol (Camb) 2011 Z, Zhao Y. Single-chain antibody-delivered Livin siRNA Apr;3(4):279-96 inhibits human malignant melanoma growth in vitro and in Sanna MG, da Silva Correia J, Luo Y, Chuang B, Paulson vivo Tumour Biol 2017 May;39(5):1010428317701645 LM, Nguyen B, Deveraux QL, Ulevitch RJ. ILPIP, a novel Wang R, Lin F, Wang X, Gao P, Dong K, Zou AM, Cheng anti-apoptotic protein that enhances XIAP-mediated SY, Wei SH, Zhang HZ. Silencing Livin gene expression to activation of JNK1 and protection against apoptosis J Biol inhibit proliferation and enhance chemosensitivity in tumor Chem 2002 Aug 23;277(34):30454-62 cells Cancer Gene Ther 2008 Jun;15(6):402-12 Shiloach T, Berens C, Danke C, Waiskopf O, Perlman R, Wang X, Xu J, Ju S, Ni H, Zhu J, Wang H. Livin gene plays Ben-Yehuda D. tLivin displays flexibility by promoting a role in drug resistance of colon cancer cells Clin Biochem alternative cell death mechanisms PLoS One 2014 Jun 2010 May;43(7-8):655-60 24;9(6):e101075 Wang Y, Li Y, Zhou B, Zhang WY, Guan JT, Wang R, Yang Slagsvold JE, Pettersen CH, Størvold GL, Follestad T, L, Xia QJ, Zhou ZG, Sun XF. Expression of the apoptosis Krokan HE, Schønberg SA. DHA alters expression of target inhibitor livin in colorectal adenoma-carcinoma sequence: proteins of cancer therapy in chemotherapy resistant correlations with pathology and outcome Tumour Biol 2014 SW620 colon cancer cells Nutr Cancer 2010;62(5):611-21 Dec;35(12):11791-8 Su QB, Wang LY, Wei GN, Liao LZ, Zhao J, Liu HJ, Shi YL, Wang Z, Liu S, Ding K, Ding S, Li C, Lu J, Gao D, Zhang T, Li LP, Li CS. Livin serves as a prognostic marker for mid- Bi D. Silencing Livin induces apoptotic and autophagic cell distal rectal cancer and a target of mid-distal rectal cancer death, increasing chemotherapeutic sensitivity to cisplatin treatment Oncol Lett 2017 Dec;14(6):7759-7766 of renal carcinoma cells Tumour Biol 2016 Sun K, Liao Q, Chen Z, Chen T, Zhang J. Expression of Nov;37(11):15133-15143 Livin and PlGF in human osteosarcoma is associated with Wu S, Zhang G, Li P, Chen S, Zhang F, Li J, Jiang C, Chen tumor progression and clinical outcome Oncol Lett 2018 X, Wang Y, Du Y, Sun Q, Zhao G. miR-198 targets SHMT1 Oct;16(4):4953-4960 to inhibit cell proliferation and enhance cell apoptosis in lung Tanabe M, Shimazu M, Wakabayashi G, Hoshino K, adenocarcinoma Tumour Biol 2016 Apr;37(4):5193-202 Kawachi S, Kadomura T, Seki H, Morikawa Y, Kitajima M. Xi RC, Biao WS, Gang ZZ. Significant elevation of survivin Intraportal infusion therapy as a novel approach to adult and livin expression in human colorectal cancer: inverse ABO-incompatible liver transplantation Transplantation correlation between expression and overall survival 2002 Jun 27;73(12):1959-61 Onkologie 2011;34(8-9):428-32 Tanhaei AP, Ziaei A, Mazrouei S, Keyhanian K, Salehi M. Xia C, Xu Z, Yuan X, Uematsu K, You L, Li K, Li L, Livin, a novel marker in lymphoma type distinction Ann McCormick F, Jablons DM. Induction of apoptosis in Diagn Pathol 2014 Jun;18(3):157-62 mesothelioma cells by antisurvivin oligonucleotides Mol Uematsu K, Kanazawa S, You L, He B, Xu Z, Li K, Peterlin Cancer Ther 2002 Jul;1(9):687-94 BM, McCormick F, Jablons DM. Wnt pathway activation in Xu W, Chang H, Qin CK, Zhai YP. Impact of Co-transfection mesothelioma: evidence of Dishevelled overexpression and with Livin and survivin shRNA expression vectors on transcriptional activity of beta-catenin Cancer Res 2003 biological behavior of HepG2 cells Asian Pac J Cancer Prev Aug 1;63(15):4547-51 2013;14(9):5467-72 Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Xue D, Zuo K, Li X, Zhang T, Chen H, Cheng Y, Chen Y. Kadkhodayan S, Fairbrother WJ, Dixit VM. SMAC Expression and prognostic significance of livin, caspase-3, negatively regulates the anti-apoptotic activity of melanoma and ki-67 in the progression of human ampullary carcinoma inhibitor of apoptosis (ML-IAP) J Biol Chem 2002 Apr Appl Immunohistochem Mol Morphol 2013 Dec;21(6):525- 5;277(14):12275-9 31 Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Yan B. Research progress on Livin protein: an inhibitor of Shin H, Elliott LO, Kadkhodayan S, Deshayes K, Salvesen apoptosis Mol Cell Biochem 2011 Nov;357(1-2):39-45 GS, Fairbrother WJ. Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Yang J, Zhao H, Xin Y, Fan L. MicroRNA-198 inhibits Smac-dependent anti-apoptotic activity of ML-IAP Biochem proliferation and induces apoptosis of lung cancer cells via J 2005 Jan 1;385(Pt 1):11-20 targeting FGFR1 J Cell Biochem 2014 May;115(5):987-95 Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit Yang YL, Lin SR, Chen JS, Lin SW, Yu SL, Chen HY, Yen VM. ML-IAP, a novel inhibitor of apoptosis that is CT, Lin CY, Lin JF, Lin KH, Jou ST, Hu CY, Chang SK, Lu preferentially expressed in human melanomas Curr Biol MY, Chang HH, Chang WH, Lin KS, Lin DT. Expression and 2000 Nov 2;10(21):1359-66 prognostic significance of the apoptotic genes BCL2L13,
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 246
BIRC7 (baculoviral IAP repeat containing 7) Botelho Rigato D et al.
Livin, and CASP8AP2 in childhood acute lymphoblastic antiapoptotic proteins livin and survivin in pediatric AML leukemia Leuk Res 2010 Jan;34(1):18-23 patients, as prognostic markers Pediatr Hematol Oncol 2018 May;35(4):250-256 Ye L, Song X, Li S, Yang D, Zhang J, Che X, Chen X, Wang J, Zhang Z. Livin-α promotes cell proliferation by regulating Zhang M, Shan BE, Yuan NF, Liu W. Effect of topotecan on G1-S cell cycle transition in prostate cancer Prostate 2011 retinocytoma cell apoptosis and expression of Livin and Jan 1;71(1):42-51 PTEN Chin Med J (Engl) 2013 Jan;126(2):340-4 Yoon TM, Kim SA, Lee DH, Lee JK, Park YL, Lee KH, Zhou J, Yuen NK, Zhan Q, Velazquez EF, Murphy GF, Chung IJ, Joo YE, Lim SC. Livin enhances chemoresistance Giobbie-Hurder A, Hodi FS. Immunity to the melanoma in head and neck squamous cell carcinoma Oncol Rep inhibitor of apoptosis protein (ML-IAP; livin) in patients with 2017 Jun;37(6):3667-3673 malignant melanoma Cancer Immunol Immunother 2012 May;61(5):655-65 Yu L, Wang Z. Effects of Livin gene RNA interference on apoptosis of cervical cancer HeLa cells and enhanced Zou AM, Wang HF, Zhu WF, Wang FX, Shen JJ. Effect of sensitivity to cisplatin J Huazhong Univ Sci Technolog Med RNAi-mediated silencing of Livin gene on biological Sci 2009 Oct;29(5):625-30 properties of colon cancer cell line LoVo Genet Mol Res 2014 May 16;13(2):3832-41 Yuan B, Ran B, Wang S, Liu Z, Zheng Z, Chen H. siRNA directed against Livin inhibits tumor growth and induces This article should be referenced as such: apoptosis in human glioma cells J Neurooncol 2012 Mar;107(1):81-7 Botelho Rigato D, Branco P C , Reis Silva CSM, Machado-Neto JA, Costa-Lotufo LV, Jimenez PC. Yuan D, Liu L, Xu H, Gu D. The effects on cell growth and BIRC7 (baculoviral IAP repeat containing 7). Atlas Genet chemosensitivity by livin RNAi in non-small cell lung cancer Cytogenet Oncol Haematol. 2020; 24(6): 234-247. Mol Cell Biochem 2009 Jan;320(1-2):133-40 Zareifar S, Ghorbani S, Monabbati A, Bordbar MR, Zekavat OR, Abdolkarimi B, Haghpanah S. Expression of
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 247
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Leukaemia Section Short Communication del(5q) in acute lymphoblastic leukemia (ALL) Adriana Zamecnikova, Soad al Bahar [email protected] (AZ); Kuwait Cancer Control Center, Kuwait (SaB)
Published in Atlas Database: August 2019
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del5qALLID1768.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70750/08-2019-del5qALLID1768.pdf DOI: 10.4267/2042/70750
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Clinics and pathology Myelodysplatic syndrome (MDS) with an isolated Disease 5q deletion (5q-syndrome), that may arise de novo or Acute lymphoblastic leukemia may be therapy-related is recognized as a distinct entity by the WHO classification. While del(5q) Etiology thought to contribute to the pathogenesis of myeloid Acute leukemia evolving from an underlying MDS neoplasms, it has also been reported in with del(5q) is almost always of myeloid lineage and lymphoblastic leukemia, suggesting a common only anecdotal case reports of MDS transforming to underlying mechanism. ALL have been reported (Agostino et al., 2011; Jain Keywords et al., 2016). Whether the presence of del(5q) in Myelodysplastic syndrome; acute lymphoblastic these cases reflects the underlying myelodysplastic leukemia; lenalidomide; 5q- syndrome; tumor state that later evolved into ALL remains unclear. suppressor genes. del(5q) in ALL is mostly associated with multiple cytogenetic abnormalities that thought to be due to Identity clonal expansion from an abnormal pluripotent stem cell. See Figure 1.
Figure 1. (A). Fluorescence in situ hybridization with Vysis LSI CSF1R (5q33-34)/5p15.2 probe (Abott Molecular/Vysis, US) showing 2 red and 2 green signals on a normal metaphase and only 1 red signal on a metaphase with 5q deletion. Inset: Partial karyotype with 5q deletion and with chromosome 5 in 'action' (chromosome 5 breaks).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 248 del(5q) in acute lymphoblastic leukemia (ALL) Zamecnikova A, al Bahar S
Epidemiology Among these patients, there was and a 5-year-old boy who had previously received chemotherapy for At least 160 reported patients aged 0 to 86 years (98 ALL that had been diagnosed nine months before males, 61 females, 1 unknown); prevalence of (Palau et al., 1991), a 13-year-old boy in whom the pediatric patients (86 patients) and there were 46 rearrangement was transiently present 7 months adults. following the diagnosis of Ph-positive ALL B-cell acute lymphoblastic leukemia: 70 patients (Theodossiou et al., 1992). aged 0 to 86 years (41 males and 28 females, 1 Del(5q)with other abnormalities Found in a unknown); among them there were 22 adults (14 sideline with del(20q) and +Y in 2 MDS patients males and 8 females, aged 22 to 86 years; median 42 transforming to B-ALL while on lenalidomide years) and 39 pediatric patients (22 males and 17 (Agostino et al., 2011) and with limited additional females, aged 0 to 18; median 6 years). In addition, anomalies such as i(7)(q10) in 1 (Kaneko et al., there were 9 patients with unknown age (5 males and 1989), +22 in 1 (Karst et al., 2006), 3 females, 1 unknown). der(19)t(1;19)(q23;p13) in 1 (Chen et al., 1992) and T-cell acute lymphoblastic leukemia: 58 patients 1 had a clone with a Ph chromosome and del(5q) at (35 males and 23 females aged 1 to 79 years); among diagnosis (Takechi et al., 1990). The them there were 17 adults (9 males and 8 females t(12;21)(p13;q22) was present as a sole additional aged 19 to 79 years), 35 pediatric patients (22 males anomaly in 3 patients with B-cell ALL (Lu et al., 13 females aged 1 to 18 years) and 6 patients with 2002; South et al., 2006; Zhou et al., 2012) and in 8 unknown age (4 males and 2 females). it was part of a complex karyotype (Alvarez et al., 32 patients had unspecified ALL (22 males, 10 2005; Kuchinskaya et al., 2005; Jarosova et al., females aged 3 to 81 years; median 13 years); 7 2003; Martineau et al., 2005; Olsson et al., 2018), patients were adults (5 males and 2 females) aged 34 however it is possible that some additional pediatric to 81 years (median 72 years), 12 were pediatric patients had a cryptic t(12;21). 3 patients had patients (8 males and 4 females aged 3 to 16 years; dic(9;20) (Heerema et al., 1996; Strefford et al., median 6 years) and there were 12 patients with 2007; An et al., 2008), 10 t(9;22) (q34;q11) unknown age (8 males and 4 females). (Sessarego et al., 1991; Tsuchiya et al., 1995; Rieder Clinics et al., 1996; Lee et al., 2002; Onciu et al., 2002; Wetzler et al., 2004; Russell et al., 2008; De In contrast to its presence in myeloid malignancies, Braekeleer et al., 2010; Lundin et al., 2014; Olsson isolated del(5q) is rare in ALL, thus its clinical et al., 2018) in complex karyotypes. The majority of significance is unknown. del(5q) also appears to be patients with T-ALL had karyotypes with clinically insignificant in patients following combination of chromosome deletions and specific cytotoxic therapy or tyrosine kinase inhibitor (TKI) translocations such as t(4;11)(q21;p15) (Hussey et therapy, similar to other clonal cytogenetic al., 1999), t(5;14)/HOX11L2 (Berger et al., 2003; abnormalities if detected as a minor clone (Tang et Bernard et al., 2001), t(4;11)(q23;p15) (Zhang et al., al., 2015). del(5q) in ALL mainly found as a clonal 2012), t(7;10)(q34;q24) (Lai et al., 2000), evolution event associated with disease progression. t(7;11)(q35;p13) (Kaneko et al. ID: >1998), t(10;11)(p12;q21) (Matlawska-Wasowska et al., Genetics 2016), t(10;14)(q24;q11) (Grossmann et al., 2013) Del(5q) may be found as sole abnormality at first, as and inv(7)(p15q34) (Rowley et al., 1999; La Starza an evolutionary event in other cases, and as a et al., 2016). transient event in patients after being treated with cytotoxic agents or TKI for the prior malignancies. Genes involved and Cytogenetics proteins Deletions of 5q are heterozygous, and deleted Cytogenetics morphological regions can affect different genes that are involved Excluded are patients with EBF1/PDGFRB in the regulation of hematopoiesis. fusion that arose from interstitial deletion of 5q33, occurring within the Philadelphia-like ALL subtype. Result of the chromosomal Del(5q) as a sole clonal cytogenetic abnormality anomaly was found in 11 patients (3 with B-ALL, 4 with T- ALL and 4 with unspecified ALL) (Kowalczyk et al., Fusion protein 1985; Brusamolino et al., 1988; Raimondi et al., 1988; Loncarevic et al., 1999; Midmer et al., 1999; Oncogenesis Gmidene et al., 2008; Palau et al., 1991; Valtat et al., Interstitial or terminal deletions of the long arm of 1991; Theodossiou et al., 1992; Goud et al., 2015).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 249
del(5q) in acute lymphoblastic leukemia (ALL) Zamecnikova A, al Bahar S
chromosome 5 are common findings in MDS or Français de Cytogénétique Hématologique (GFCH). acute myeloid leukemia (AML), but they may also Leukemia. 2003 Sep;17(9):1851-7 occur in patients with ALL. Deletions of genetic Bernard OA, Busson-LeConiat M, Ballerini P, Mauchauffé material from 5q result in loss of tumor suppressor M, Della Valle V, Monni R, Nguyen Khac F, Mercher T, Penard-Lacronique V, Pasturaud P, Gressin L, Heilig R, genes that may potentially play a role in the Daniel MT, Lessard M, Berger R. A new recurrent and pathogenesis of these diseases. The long arm of specific cryptic translocation, t(5;14)(q35;q32), is chromosome 5 contains many genes that are relevant associated with expression of the Hox11L2 gene in T acute in hematopoiesis and several candidate genes lymphoblastic leukemia Leukemia 2001 Oct;15(10):1495- including transcription factors, cytokines and their 504 receptors, signal mediators and cell cycle regulators Brusamolino E, Orlandi E, Morra E, Bernasconi P, have been identified. These include the RPS14 gene Pagnucco G, Colombo A, Lazzarino M, Bernasconi C. Hematologic and clinical features of patients with on 5q33.1, a critical gene for the erythroid chromosome 5 monosomy or deletion (5q) Med Pediatr phenotype, a microRNA cluster on 5q32-33 Oncol 1988;16(2):88-94 important for the megakaryocytic phenotype, the Chen Z, Morgan R, Sandberg AA. Non-random involvement EGR1 gene on 5q31 that plays a role in of chromosome 5 in ALL Cancer Genet Cytogenet 1992 Jul hematopoietic stem cell proliferation. Other genes 1;61(1):106-7 such as NPM1 and APC, the transcription factor De Braekeleer E, Douet-Guilbert N, Morel F, Le Bris MJ, Egr1/Krox20, the cytoskeletal remodeling protein, Basinko A, Berthou C, Morice P, Férec C, De Braekeleer alpha-catenin may also contribute to the disease M. Philadelphia chromosome-positive acute lymphoblastic phenotype and progression (Tang et al., 2015). leukemia: a cytogenetic study of 33 patients diagnosed between 1981 and 2008 Anticancer Res 2010 Although a critical tumor suppressor gene has not yet Feb;30(2):569-73 been identified in ALL, several putative tumor suppressors such as NR3C1 and TCF7, located Faderl S, Gidel C, Kantarjian HM, Manshouri T, Keating M, Albitar M. Loss of heterozygosity on chromosome 5 in adults within the 5q31 common deleted region and with acute lymphoblastic leukemia Leuk Res 2001 TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, Jan;25(1):39-43 mapping at 5q35 have been found to be down- Gmidène A, Sennana H, Elghezal H, Ziraoui S, Youssef YB, regulated in T- ALL (La Starza et al.,2016). Given Elloumi M, Issaoui L, Harrabi I, Raynaud S, Saad A. the large size and variable pattern of 5q deletions, it Cytogenetic analysis of 298 newly diagnosed cases of acute is probable that the loss of several genes that act lymphoblastic leukaemia in Tunisia Hematol Oncol 2008 alone or in combination contribute to pathogenesis. Jun;26(2):91-7 The absence of a clear critical gene suggests that Goud TM, Al Salmani KK, Al Harasi SM, Al Musalhi M, deletion of variable combinations of genes may Wasifuddin SM, Rajab A. Importance of FISH combined with Morphology, Immunophenotype and Cytogenetic result in a clinical spectrum ranging from myeloid Analysis of Childhood/ Adult Acute Lymphoblastic malignancies to lymphoid leukemia. Leukemia in Omani Patients Asian Pac J Cancer Prev 2015;16(16):7343-50 References Grossmann V, Haferlach C, Weissmann S, Roller A, Schindela S, Poetzinger F, Stadler K, Bellos F, Kern W, Agostino NM, Ahmed B, Popescu D, Gheith S. Haferlach T, Schnittger S, Kohlmann A. The molecular Transformation of the 5q- syndrome to acute lymphoblastic profile of adult T-cell acute lymphoblastic leukemia: leukemia: a report of two cases and review of the literature. mutations in RUNX1 and DNMT3A are associated with poor Int J Clin Exp Pathol. 2011 Mar;4(3):322-6 prognosis in T-ALL Genes Chromosomes Cancer 2013 Alvarez Y, Coll MD, Ortega JJ, Bastida P, Dastugue N, Apr;52(4):410-22 Robert A, Cervera J, Verdeguer A, Tasso M, Aventín A, Heerema NA, Sather HN, Sensel MG, Kraft P, Nachman JB, Guitart M, Caballín MR. Genetic abnormalities associated Steinherz PG, Lange BJ, Hutchinson RS, Reaman GH, with the t(12;21) and their impact in the outcome of 56 Trigg ME, Arthur DC, Gaynon PS, Uckun FM. Frequency patients with B-precursor acute lymphoblastic leukemia. and clinical significance of cytogenetic abnormalities in Cancer Genet Cytogenet. 2005 Oct 1;162(1):21-9 pediatric T-lineage acute lymphoblastic leukemia: a report An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman from the Children's Cancer Group J Clin Oncol 1998 AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Apr;16(4):1270-8 Harrison CJ, Irving JA, Strefford JC. Variable breakpoints Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A. The target PAX5 in patients with dicentric chromosomes: a (4;11)(q21;p15) translocation fuses the NUP98 and model for the basis of unbalanced translocations in cancer. RAP1GDS1 genes and is recurrent in T-cell acute Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4 lymphocytic leukemia Blood 1999 Sep 15;94(6):2072-9 Berger R, Dastugue N, Busson M, Van Den Akker J, Pérot Jain P, Tang G, Konoplev SN, Kanagal-Shamanna R, Wang C, Ballerini P, Hagemeijer A, Michaux L, Charrin C, Pages SA, Pemmaraju N, Daver N, Estrov Z. Synchronous del5q MP, Mugneret F, Andrieux J, Talmant P, Hélias C, Mauvieux myelodysplastic syndrome (del5qMDS) and adult B-cell L, Lafage-Pochitaloff M, Mozziconacci MJ, Cornillet- acute lymphoblastic leukemia (B-ALL) with TET2 and TP53 Lefebvre P, Radford I, Asnafi V, Bilhou-Nabera C, Nguyen mutations Am J Hematol 2016 Mar;91(3):354-5 Khac F, Léonard C, Speleman F, Poppe B, Bastard C, Taviaux S, Quilichini B, Herens C, Grégoire MJ, Cavé H, Jarosova M, Volejnikova J, Porizkova I, Holzerova M, Bernard OA. t(5;14)/HOX11L2-positive T-cell acute Pospisilova D, Novak Z, Vrbkova J, Mihal V. Chromosomal lymphoblastic leukemia. A collaborative study of the Groupe aberrations in childhood acute lymphoblastic leukemia: 15-
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 250
del(5q) in acute lymphoblastic leukemia (ALL) Zamecnikova A, al Bahar S
year single center experience Cancer Genet 2016 Jul- relapse: some prognostic indications Genes Chromosomes Aug;209(7-8):340-7 Cancer 2005 May;43(1):54-71 Kaneko Y, Frizzera G, Shikano T, Kobayashi H, Maseki N, Matlawska-Wasowska K, Kang H, Devidas M, Wen J, Sakurai M. Chromosomal and immunophenotypic patterns Harvey RC, Nickl CK, Ness SA, Rusch M, Li Y, Onozawa in T cell acute lymphoblastic leukemia (T ALL) and M, Martinez C, Wood BL, Asselin BL, Chen IM, Roberts KG, lymphoblastic lymphoma (LBL) Leukemia 1989 Baruchel A, Soulier J, Dombret H, Zhang J, Larson RS, Dec;3(12):886-92 Raetz EA, Carroll WL, Winick NJ, Aplan PD, Loh ML, Mullighan CG, Hunger SP, Heerema NA, Carroll AJ, Kaneko Y, Maseki N, Homma C, Sakurai M, Mizutani S, Dunsmore KP, Winter SS. MLL rearrangements impact Takeda T, Shikano T, Fujimoto T, Yaoi K, Shimokawa T. outcome in HOXA-deregulated T-lineage acute Chromosome translocations involving band 7q35 or 7p15 in lymphoblastic leukemia: a Children's Oncology Group Study childhood T-cell leukemia/lymphoma Blood 1988 Leukemia 2016 Sep;30(9):1909-12 Aug;72(2):534-8 Midmer M, Haq R, Squire JA, Zanke BW. Identification of Karst C, Gross M, Haase D, Wedding U, Höffken K, Liehr T, NKIAMRE, the human homologue to the mitogen-activated Mkrtchyan H. Novel cryptic chromosomal rearrangements protein kinase-/cyclin-dependent kinase-related protein detected in acute lymphoblastic leukemia detected by kinase NKIATRE, and its loss in leukemic blasts with application of new multicolor fluorescent in situ hybridization chromosome arm 5q deletion Cancer Res 1999 Aug approaches Int J Oncol 2006 Apr;28(4):891-7 15;59(16):4069-74 Kowalczyk J, Sandberg AA. A possible subgroup of ALL Olsson L, Albitar F, Castor A, Behrendtz M, Biloglav A, with 9p- Cancer Genet Cytogenet 1983 Aug;9(4):383-5 Paulsson K, Johansson B. Cooperative genetic changes in Kuchinskaya E, Heyman M, Grandér D, Linderholm M, pediatric B-cell precursor acute lymphoblastic leukemia Söderhäll S, Zaritskey A, Nordgren A, Porwit-Macdonald A, with deletions or mutations of IKZF1 Genes Chromosomes Zueva E, Pawitan Y, Corcoran M, Nordenskjöld M, Blennow Cancer 2015 May;54(5):315-25 E. Children and adults with acute lymphoblastic leukaemia Olsson L, Lundin-Ström KB, Castor A, Behrendtz M, have similar gene expression profiles Eur J Haematol 2005 Biloglav A, Norén-Nyström U, Paulsson K, Johansson B. Jun;74(6):466-80 Improved cytogenetic characterization and risk stratification La Starza R, Barba G, Demeyer S, Pierini V, Di Giacomo D, of pediatric acute lymphoblastic leukemia using single Gianfelici V, Schwab C, Matteucci C, Vicente C, Cools J, nucleotide polymorphism array analysis: A single center Messina M, Crescenzi B, Chiaretti S, Foà R, Basso G, experience of 296 cases Genes Chromosomes Cancer Harrison CJ, Mecucci C. Deletions of the long arm of 2018 Nov;57(11):604-607 chromosome 5 define subgroups of T-cell acute Onciu M, Bueso-Ramos C, Medeiros LJ, Ball G, Smith T, lymphoblastic leukemia Haematologica 2016 Lai R. Acute lymphoblastic leukemia in elderly patients the Aug;101(8):951-8 Philadelphia chromosome may not be a significant adverse Lai R, Juco J, Lee SF, Nahirniak S, Etches WS. Flow prognostic factor Am J Clin Pathol 2002 May;117(5):716- cytometric detection of CD79a expression in T-cell acute 20 lymphoblastic leukemias Am J Clin Pathol 2000 Palau F, Prieto F, Badia L, Beneyto M, Benet I. Jun;113(6):823-30 Chromosome 5 abnormalities in acute lymphoblastic Lee S, Kim DW, Kim YJ, Park YH, Min CK, Lee JW, Min leukemia Cancer Genet Cytogenet 1991 Apr;52(2):173-9 WS, Kim CC. Influence of karyotype on outcome of Raimondi SC, Behm FG, Roberson PK, Pui CH, Rivera GK, allogeneic bone marrow transplantation for adults with Murphy SB, Williams DL. Cytogenetics of childhood T-cell precursor B-lineage acute lymphoblastic leukaemia in first leukemia Blood 1988 Nov;72(5):1560-6 or second remission Br J Haematol 2002 Apr;117(1):109- 18 Rieder H, Ludwig WD, Gassmann W, Maurer J, Janssen JW, Gökbuget N, Schwartz S, Thiel E, Löffler H, Bartram Loncarevic IF, Roitzheim B, Ritterbach J, Viehmann S, CR, Hoelzer D, Fonatsch C. Prognostic significance of Borkhardt A, Lampert F, Harbott J. Trisomy 21 is a recurrent additional chromosome abnormalities in adult patients with secondary aberration in childhood acute lymphoblastic Philadelphia chromosome positive acute lymphoblastic leukemia with TEL/AML1 gene fusion Genes Chromosomes leukaemia Br J Haematol 1996 Dec;95(4):678-91 Cancer 1999 Mar;24(3):272-7 Rowley JD, Reshmi S, Carlson K, Roulston D. Spectral Lu XY, Harris CP, Cooley L, Margolin J, Steuber PC, karyotype analysis of T-cell acute leukemia Blood 1999 Mar Sheldon M, Rao PH, Lau CC. The utility of spectral 15;93(6):2038-42 karyotyping in the cytogenetic analysis of newly diagnosed pediatric acute lymphoblastic leukemia Leukemia 2002 Russell LJ, Akasaka T, Majid A, Sugimoto KJ, Loraine Nov;16(11):2222-7 Karran E, Nagel I, Harder L, Claviez A, Gesk S, Moorman AV, Ross F, Mazzullo H, Strefford JC, Siebert R, Dyer MJ, Lundin C, Forestier E, Klarskov Andersen M, Autio K, Harrison CJ. t(6;14)(p22;q32): a new recurrent IGH@ Barbany G, Cavelier L, Golovleva I, Heim S, Heinonen K, translocation involving ID4 in B-cell precursor acute Hovland R, Johannsson JH, Kjeldsen E, Nordgren A, lymphoblastic leukemia (BCP-ALL) Blood 2008 Jan Palmqvist L, Johansson B; Nordic Society of Pediatric 1;111(1):387-91 Hematology Oncology (NOPHO); Swedish Cytogenetic Leukemia Study Group (SCLSG); NOPHO Leukemia Sessarego M, Defferrari R, Fugazza G, Comelli A, Salvidio Cytogenetic Study Group (NLCSG). Clinical and genetic E, Ajmar F. Involvement of the short arm of the derivative features of pediatric acute lymphoblastic leukemia in Down chromosome 9 in Philadelphia-positive acute lymphoblastic syndrome in the Nordic countries J Hematol Oncol 2014 leukemia Cancer Genet Cytogenet 1991 Mar;52(1):43-9 Apr 11;7:32 South ST, Frazer JK, Brothman AR, Chen Z. Unexpected Martineau M, Jalali GR, Barber KE, Broadfield ZJ, Cheung cytogenetic finding in acute lymphoblastic leukemia: a case KL, Lilleyman J, Moorman AV, Richards S, Robinson HM, of del(5q) with a cryptic t(12;21) Cancer Genet Cytogenet Ross F, Harrison CJ. ETV6/RUNX1 fusion at diagnosis and 2006 Jul 15;168(2):177-8
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 251
del(5q) in acute lymphoblastic leukemia (ALL) Zamecnikova A, al Bahar S
Strefford JC, Worley H, Barber K, Wright S, Stewart AR, Tantravahi R, Vardiman JW, Larson RA, Bloomfield CD. Robinson HM, Bettney G, van Delft FW, Atherton MG, Additional cytogenetic abnormalities in adults with Davies T, Griffiths M, Hing S, Ross FM, Talley P, Saha V, Philadelphia chromosome-positive acute lymphoblastic Moorman AV, Harrison CJ. Genome complexity in acute leukaemia: a study of the Cancer and Leukaemia Group B lymphoblastic leukemia is revealed by array-based Br J Haematol 2004 Feb;124(3):275-88 comparative genomic hybridization Oncogene 2007 Jun 21;26(29):4306-18 Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne- Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen Takechi M, Ohnishi A, Tanaka K, Kimura N, Kamada N. SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Acute T-lymphocytic leukemia with Ph1 and 5q- Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, chromosome abnormalities and rearrangements of bcr and Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, TCR-delta genes Leuk Res 1990;14(10):885-93 Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Tang G, Goswami RS, Liang CS, Bueso-Ramos CE, Hu S, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston DiNardo C, Medeiros LJ. Isolated del(5q) in Patients ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Following Therapies for Various Malignancies May Not All Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter Be Clinically Significant Am J Clin Pathol 2015 S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Jul;144(1):78-86 Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans Theodossiou C, Scalise A, Troy K, Silverman L, Perdahl- WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Wallace E, Najfeld V. del(5q) in acute lymphoblastic Downing JR, Mullighan CG. The genetic basis of early T- leukemia with biphenotypic and early progenitor phenotype cell precursor acute lymphoblastic leukaemia Nature 2012 Cancer Genet Cytogenet 1992 Oct 15;63(2):89-94 Jan 11;481(7380):157-63 Tsuchiya H, Migita M, Yamamori S, Kaneko Y, Adachi N, Zhou MH, Gao L, Jing Y, Xu YY, Ding Y, Wang N, Wang W, Nakamura T, Nobukuni Y, el-Sonbaty SS, Matsuda I. A Li MY, Han XP, Sun JZ, Wang LL, Yu L. Detection of ETV6 late-appearing Philadelphia chromosome in acute gene rearrangements in adult acute lymphoblastic leukemia lymphoblastic leukemia confirmed by expression of BCR- Ann Hematol 2012 Aug;91(8):1235-43 ABL mRNA Leukemia 1995 Oct;9(10):1689-93 This article should be referenced as such: Valtat C, Uettwiller F, Flori E, Valtat B, Ruch JV, Oberling F. Mosaic 46,XY/92,XXYY,del(5)(q13 q34) in an adult Zamecnikova A, al Bahar S. del(5q) in acute lymphoblastic leukemia Leuk Res 1991;15(7):651-3 lymphoblastic leukemia (ALL). Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6):248-252. Wetzler M, Dodge RK, Mrózek K, Stewart CC, Carroll AJ,
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 252
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Leukaemia Section Short Communication t(14;19)(q11;q13) TRA/NECTIN2 Jean Loup Huret [email protected]
Published in Atlas Database: September 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1419q11q13TRANECTIN2ID1513.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70751/09-2019-t1419q11q13TRANECTIN2ID1513.pdf DOI: 10.4267/2042/70751
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Note Abstract NECTIN2 is also called PVRL2 (poliovirus Review on t(14;19)(q11;q13), with data on clinics, receptor-related 2). and the genes involved. Protein Keywords NECTIN2 is a cell membrane protein involved in Chromosome 14; chromosome 19; TRA; NECTIN2; immune checkpoint, part of the TIGIT-PVR/PVRL2 peripheral T-cell lymphoma; angioimmunoblastic T- axis. NECTIN2 is composed of a signal peptide cell lymphoma. (amino acids (aa) 1-31), an extracellular domain (aa 32-360), a transmembrane domain (aa 361-381), and Clinics and pathology a cytoplasmic domain (aa 382-538). NECTIN2 also interacts with PVRIG CD226, CD96 to stimulate or Disease inhibit lymphocyte cell signaling (Stamm et al., 2018; Whelan et al., 2019). T-cell lymphomas Epidemiology Result of the chromosomal Four cases available to date: three peripheral T-cell anomaly lymphoma not otherwise specified (PTCL-NOS) (two male patients aged 20 and 63 yrs and one Hybrid gene female patient aged 63 yrs), and one On chromosome 19, there was a cluster of angioimmunoblastic T-cell lymphoma (Lepretre et breakpoints in the NECTIN2 gene region, 130 kb al., 2000; Almire et al., 2007; Shin et al., 212). downstream of BCL3. The breakpoints on chromosome 14 were located in theTRAJ region Cytogenetics (Almire et al., 2007). Cytogenetics morphological Fusion protein The karyotype was complex in all four cases. Oncogenesis NECTIN2 was highly expressed in the Genes involved and t(14;19)(q11;q13)-positive tumors. proteins References TRA (T cell Receptor Alpha) Almire C, Bertrand P, Ruminy P, Maingonnat C, Wlodarska Location 14q11.2 I, Martín-Subero JI, Siebert R, Tilly H, Bastard C. PVRL2 is translocated to the TRA@ locus in t(14;19)(q11;q13)- NECTIN2 (nectin cell adhesion positive peripheral T-cell lymphomas Genes Chromosomes molecule 2) Cancer 2007 Nov;46(11):1011-8 Ehrentraut S, Nagel S, Pommerenke C, Dirks WG, Location 19q13.32 Quentmeier H, Kaufmann M, Meyer C, Zaborski M, Geffers
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 253 t(14;19)(q11;q13) TRA/NECTIN2 Huret JL
R, Fujiwara H, Drexler HG, MacLeod RAF. Peripheral T-cell PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune lymphoma cell line T8ML-1 highlights conspicuous targeting checkpoint axis and therapeutic target in cancer Mamm of PVRL2 by t(14;19)(q11 2;q13 3) Genome 2018 Dec;29(11-12):694-702 Lepretre S, Buchonnet G, Stamatoullas A, Lenain P, Duval Whelan S, Ophir E, Kotturi MF, Levy O, Ganguly S, Leung C, d'Anjou J, Callat M-P, Tilly H, Bastard C,. Chromosome L, Vaknin I, Kumar S, Dassa L, Hansen K, Bernados D, abnormalities in peripheral T-cell lymphoma. Cancer Genet Murter B, Soni A, Taube JM, Fader AN, Wang TL, Shih IM, Cytogenet 2000; 117:71-79. White M, Pardoll DM, Liang SC. PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8(+) T-cell Function Shin SY, Jang S, Park CJ, Chi HS, Lee KH, Huh J, Seo EJ. Cancer Immunol Res 2019 Feb;7(2):257-268 A rare case of Lennert's type peripheral T-cell lymphoma with t(14;19)(q11 2;q13 3) This article should be referenced as such: Stamm H, Wellbrock J, Fiedler W. Interaction of Huret JL. t(14;19)(q11;q13) TRA/NECTIN2. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6):253-254.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 254
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Leukaemia Section Short Communication t(14;19)(q32;q13) IGH/Various Partners Jean Loup Huret [email protected] Published in Atlas Database: September 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1419ID1462.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70752/09-2019-t1419ID1462.pdf DOI: 10.4267/2042/70752
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
A t(14;19)(q32;q13) IGH/CEBPA or CEBPG, but Abstract also other translocations with IGH fused to Review on the various t(14;19)(q32;q13), with data CCAAT/enhancer binding proteins (CEBPB on clinics, and the genes involved. (20q13), CEBPD (8p11), CEBPE (14q11)) has been Keywords found so far only in acute B-cell lymphoblastic leukemia. Chromosome 14; chromosome 19; IGH; BCL3; Other t(14;19)(q32;q13) with IGH involvement CEBPA; CEBPG; ERF; FOSB; NECTIN2; have been found in multiple myeloma (IGH/ERF, PPP1R15A; SPIB; chronic lymphocytic leukemia; IGH/FOSB, IGH/PPP1R15A (Cleynen et al., 2017)) nodal marginal zone B-cell lymphoma; mature B- and diffuse large B-cell lymphoma (IGH/NECTIN2, cell neoplasm; diffuse large B-cell lymphoma; IGH/SPIB (Lenz et al 2007; Otto et al., 2016)). splenic marginal zone B-cell lymphoma; follicular lymphoma; bilineage leukemia; Burkitt lymphoma; Cytogenetics chronic myeloid leukemia; lymphoplasmacytic t(14;19)(q32;q13) IGH/BCL3 lymphoma; mantle cell lymphoma; Hodgkin disease, t(14;19)(q32;q13) IGH/CEBPA or CEBPG multiple myeloma. t(14;19)(q32;q13)IGH/ERF t(14;19)(q32;q13) IGH/FOSB Clinics and pathology t(14;19)(q32;q13) IGH/NECTIN2 t(14;19)(q32;q13) IGH/PPP1R15A Disease t(14;19)(q32;q13) IGH/SPIB According to a search in Mitelman database "Cases Quick Searcher", 181 cases of t(14;19)(q32;q13) are Cytogenetics available in the literature: 104 chronic lymphocytic leukemia cases (CLL), 30 acute B-cell Cytogenetics morphological lymphoblastic leukemia, 13 nodal marginal zone B- IGH partners in the t(14;19)(q32;q13) cell lymphoma, 12 mature B-cell neoplasm not Gene Chrom. Band Starts-Ends (from pter) otherwise specified (NOS), 10 diffuse large B-cell lymphoma, 5 splenic marginal zone B-cell CEBPA 19q13.11 33,299,934 - 33,302,564 lymphoma, 2 follicular lymphoma, 1 bilineage CEBPG 19q13.11 33,373,669 - 33,382,686 leukemia, 1 Burkitt lymphoma, 1 chronic myeloid ERF 19q13.2 42,247,561 - 42,255,164 leukemia, 1 lymphoplasmacytic lymphoma, and 1 BCL3 19q13.32 44,748,721 - 44,760,044 mantle cell lymphoma. A t(14;19)(q32;q13) IGH/BCL3 has been found in NECTIN2 19q13.32 44,846,136 - 44,878,941 chronic lymphocytic leukemia, mature B-cell FOSB 19q13.32 45,467,995 - 45,475,179 neoplasm NOS, diffuse large B-cell lymphoma, PPP1R15A 19q13.33 48,872,392 - 48,876,062 bilineage leukemia, follicular lymphoma, Hodgkin disease, nodal marginal zone B-cell lymphoma, and SPIB 19q13.33 50,418,938 - 50,431,052 splenic marginal zone B-cell lymphoma.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 255 t(14;19)(q32;q13) IGH/Various Partners Huret JL
CEBPA (CCAAT/enhancer binding protein (C/EBP), alpha) Location 19q13.11 Starts at 33299934 and ends at 33302564 bp from pter. Protein 358 amino acids. CEBPA contains a bzip (aa 282- 345, with a basic motif (aa 286-313) and a leucine zipper (aa 317-345)). Transcription factor. Binds the consensus DNA sequence T[TG]NNGNAA[TG] as a homo or heterodimer. Key factor driving myeloid cell differentiation of hematopoietic stem cells and also driving differentiation of other cell lineages (Tian and Graf, 2014). CEBPG (CCAAT enhancer binding protein gamma) Location 19q13.11 Starts at 33373669 and ends at 33382686 bp from pter. CEBPG is located only 71 kb distal of CEBPA. Protein 150 amino acids. CEBPAG contains a bzip (aa 62- 125, with a basic motif (aa 66-93) and a leucine zipper (aa 97-118)). Transcription factor. CEBPB homodimers are cytostatic and promote cell cycle arrest and senescence. Conversely, CEBPB/CEBPG Genes involved and heterodimers display reduced transcriptional proteins potential. However, CEBPG deletion did not alter hematopoietic stem and progenitor cell ability to IGH (immunoglobulin heavy locus) commit to the myeloid lineage. ATF4/CEBPG Location 14q32.33 heterodimer is an antioxidant regulator that controls redox homeostasis in normal and cancerous cells. BCL3 (BCL3 transcription CEBPG acts as a negative regulator of senescence coactivator) and promotes proliferation of multiple cell types Location 19q13.32 (Huggins et al., 2013; Huggins et al., 2015; Starts at 44748721 and ends at 44760044 bp from Kardosova et al., 2018). pter. ERF (ETS2 repressor factor) Protein 454 amino acids (aa). BCL3 contains seven ankyrin Location 19q13.2 repeats (aa 134-163, 171-200, 204-235, 241-270, Starts at 42247561 and ends at 42255164 bp from 275-304, 308-337, 338-367). BCL3 is a member of pter. the I-kappaB family (NFKBIA (NFKB inhibitor Protein alpha), NFKBIB (NFKB inhibitor beta) and others), 548 amino acids. ERF contains an ETS domain (aa whose proteins regulate the NF-kB family of 29-106), an ERK interaction domain (aa 294-385), transcription factors. BCL3 interacts with NFKB1 and a repressor domain (aa 472-530). Member of the and NFKB2 (NF-kappaB p50 and p52). NF-kB plays ETS family of transcription factors. ERF a major role in B-cell development. BCL3 is induced translocates to the nucleus, where it binds to by LIF and plays a role in the maintenance of enhancers of RAS targets, pluripotency and pluripotency. BCL3 stimulates cell-cycle mitogenic factors. ERF may play a role in limiting progression in a breast cancer cell line. BCL3 mouse embryonic stem cells differentiation. Loss-of- interacts with TRAF6. The ankyrin repeats of BCL3 function ERF germline mutations are implicated in bind the RING domain of TRAF6. TRAF6 mediate an autosomal form of craniosynostosis (Mayor-Ruiz a NF-kB signaling via BCL3 to promote et al., 2018). osteoclastogenesis (Otsuka et al., 2018; Wang et al., 2018)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 256
t(14;19)(q32;q13) IGH/Various Partners Huret JL
FOSB (FosB proto-oncogene, AP-1 SPIB (Spi-B transcription factor) transcription factor subunit) Location 19q13.33 Location 19q13.32 Starts at 50418938 and ends at 50431052 bp from Starts at 45467995 and ends at 45475179 bp from pter. pter. Protein FOSB is also called AP-1 (which is confusing with 262 amino acids. SPIB contains two transactivation the "AP-1 complex"). domains (aa 1-31 and 41-61). Binds to the nucleotide Protein sequence GGAA. Transcriptional activator of B-cell 338 amino acids. FOSB contains a bzip (aa 155-218, development and differentiation. SPI1 (spleen focus with a basic motif (aa 157-182) and a leucine zipper forming virus (SFFV) proviral integration oncogene (aa 183-211)). Transcription factor, member of the spi1, also known as PU.1) and SPIB control many AP-1 Transcription Factors family: AP-1 complex is components of the B-cell receptor (BCR) pathway. a dimeric complex composed of members from the SPI1 and SPIB are partially redundant. Inactivation JUN, FOS (FOS, FOSB, FOSL1 and FOSL2 (FRA- of SPI1 and SPIB in B-cell progenitors blocks the 1 and FRA-2)), ATF, or MAF protein families. The development at the pre-B-cell stage and induces pre- sequence elements to which AP-1 transcription B acute lymphoblastic leukemia. Inactivation SPI1 factors bind differ depending on the distinctive and SPIB in mature B cells prevents germinal centers homo- or hetero-dimer combinations. FOS proteins development. SPI1 and SPIB negatively regulate bind the TRE sequence: TGACTCA. FOS proteins plasma cell differentiation (Willis et al., 2017). only form hetero-dimers (review in Garces de Los Fayos Alonso et al., 2018). Result of the chromosomal ΔFosB, a splice variant of FOSB is induced by stress, anomaly antidepressants, and drugs abuse in brain regions such as the prefrontal cortex and the hippocampus Hybrid gene (Palafox-Sanchez et al., 2019). Description NECTIN2 (nectin cell adhesion CEBPA and CEBPG cases: The breakpoints molecule 2) clustered within the 3' UTR of CEBPA in most cases, Location 19q13.32 and was 31 kb centromeric of CEBPA in one case. Starts at 44846136 and ends at 44878941 bp from The breakpoint was 52 kb centromeric of CEBPG pter. (Akasaka et al., 2007). NECTIN2 case: The NECTIN2 is also called PVRL2 (poliovirus breakpoint in NECTIN2 was located in exon 1 in the receptor-related 2). 5'untranslated region at position 45,349,458 from the p terminus of chromosome 19 (Otto et al., 2016). Protein NECTIN2 is a cell membrane protein involved in Fusion protein immune checkpoint, part of the TIGIT-PVR/PVRL2 Oncogenesis axis. NECTIN2 is composed of a signal peptide In the case reported by Otto et al., 2016, NECTIN2 (amino acids 1-31), an extracellular domain (aa 32- was expressed at a significantly higher level than in 360), a transmembrane domain (aa 361-381), and a the other 363 DLBCL studied. cytoplasmic domain (aa 382-538). NECTIN2 also interacts with PVRIG CD226, CD96 to stimulate or References inhibit lymphocyte cell signaling (Stamm et al., Tian TV, Graf TS. CEBPA (CCAAT/enhancer binding 2018; Whelan et al., 2019). protein (C/EBP), alpha) Atlas Genet Cytogenet Oncol PPP1R15A (protein phosphatase 1 Haematol. 2015;19(4):249-255. regulatory subunit 15A) Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R, Karran EL, Brown DG, Cain K, Harder L, Gesk Location 19q13.33 S, Martin-Subero JI, Atherton MG, Brüggemann M, Starts at 48872392 and ends at 48876062 bp from Calasanz MJ, Davies T, Haas OA, Hagemeijer A, Kempski pter H, Lessard M, Lillington DM, Moore S, Nguyen-Khac F, Radford-Weiss I, Schoch C, Struski S, Talley P, Welham PPP1R15A is also called GADD34. MJ, Worley H, Strefford JC, Harrison CJ, Siebert R, Dyer Protein MJ. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell 674 amino acids. PPP1R15A inhibits the precursor acute lymphoblastic leukemia (BCP-ALL) Blood proteasomal degradation of MCL1 and enhances 2007 Apr 15;109(8):3451-61 MCL1 protein stability. PPP1R15A overexpression Cleynen A, Szalat R, Kemal Samur M, Robiou du Pont S, promotes MAPK signaling pathway through TRAF6 Buisson L, Boyle E, Chretien ML, Anderson K, Minvielle S, and TAB1, which mediates the up-regulation of Moreau P, Attal M, Parmigiani G, Corre J, Munshi N, Avet- MCL1 (Song et al., 2019).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 257
t(14;19)(q32;q13) IGH/Various Partners Huret JL
Loiseau H. Expressed fusion gene landscape and its impact Lymphomas Network Project. Novel IGH and MYC in multiple myeloma Nat Commun 2017 Dec 1;8(1):1893 Translocation Partners in Diffuse Large B-Cell Lymphomas Genes Chromosomes Cancer 2016 Dec;55(12):932-943 Garces de Los Fayos Alonso I, Liang HC, Turner SD, Lagger S, Merkel O, Kenner L. The Role of Activator Palafox-Sanchez V, Sosti V, Ramirez-García G, Kulisevsky Protein-1 (AP-1) Family Members in CD30-Positive J, Aguilera J, Limón ID. Differential Expression of Striatal Lymphomas Cancers (Basel) 2018 Mar 28;10(4) FosB mRNA and FosB mRNA After Different Levodopa Treatment Regimens in a Rat Model of Parkinson's Disease Huggins CJ, Mayekar MK, Martin N, Saylor KL, Gonit M, Neurotox Res 2019 Apr;35(3):563-574 Jailwala P, Kasoji M, Haines DC, Quiñones OA, Johnson PF. C/EBPγ Is a Critical Regulator of Cellular Stress Song P, Yang S, Hua H, Zhang H, Kong Q, Wang J, Luo T, Response Networks through Heterodimerization with ATF4 Jiang Y. The regulatory protein GADD34 inhibits TRAIL- Mol Cell Biol 2015 Dec 14;36(5):693-713 induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells J Biol Chem Kardosova M, Zjablovskaja P, Danek P, Angelisova P, de 2019 Apr 12;294(15):5945-5955 Figueiredo-Pontes LL, Welner RS, Brdicka T, Lee S, Tenen DG, Alberich-Jorda M. C/EBPγ is dispensable for steady- Stamm H, Wellbrock J, Fiedler W. Interaction of state and emergency granulopoiesis Haematologica 2018 PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune Aug;103(8):e331-e335 checkpoint axis and therapeutic target in cancer Mamm Genome 2018 Dec;29(11-12):694-702 Lenz G, Nagel I, Siebert R, Roschke AV, Sanger W, Wright GW, Dave SS, Tan B, Zhao H, Rosenwald A, Muller- Wang K, Li S, Gao Y, Feng X, Liu W, Luo R, Song Y, Ji Tu, Hermelink HK, Gascoyne RD, Campo E, Jaffe ES, Smeland Liu Y, Yang C. BCL3 regulates RANKL-induced EB, Fisher RI, Kuehl WM, Chan WC, Staudt LM. Aberrant osteoclastogenesis by interacting with TRAF6 in bone immunoglobulin class switch recombination and switch marrow-derived macrophages Bone 2018 Sep;114:257- translocations in activated B cell-like diffuse large B cell 267 lymphoma J Exp Med 2007 Mar 19;204(3):633-43 Whelan S, Ophir E, Kotturi MF, Levy O, Ganguly S, Leung Mayor-Ruiz C, Olbrich T, Drosten M, Lecona E, Vega- L, Vaknin I, Kumar S, Dassa L, Hansen K, Bernados D, Sendino M, Ortega S, Dominguez O, Barbacid M, Ruiz S, Murter B, Soni A, Taube JM, Fader AN, Wang TL, Shih IM, Fernandez-Capetillo O. ERF deletion rescues RAS White M, Pardoll DM, Liang SC. PVRIG and PVRL2 Are deficiency in mouse embryonic stem cells Genes Dev 2018 Induced in Cancer and Inhibit CD8(+) T-cell Function Apr 1;32(7-8):568-576 Cancer Immunol Res 2019 Feb;7(2):257-268 Otsuka K, Takehara A, Chiba N, Matsui Y. Identification of Willis SN, Tellier J, Liao Y, Trezise S, Light A, O'Donnell K, KLF9 and BCL3 as transcription factors that enhance Garrett-Sinha LA, Shi W, Tarlinton DM, Nutt SL. reprogramming of primordial germ cells PLoS One 2018 Environmental sensing by mature B cells is controlled by the Oct 4;13(10):e0205004 transcription factors PU 1 and SpiB Nat Commun
Otto C, Scholtysik R, Schmitz R, Kreuz M, Becher C, This article should be referenced as such: Hummel M, Rosenwald A, Trümper L, Klapper W, Siebert R, Küppers R; 'Molecular Mechanisms in Malignant Huret JL. t(14;19)(q32;q13) IGH/Various Partners. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6):255-258.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 258
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Case Report Section
B-cell acute lymphoblastic leukemia with t(2;9)(p11;p13) involving the immunoglobulin kappa locus (IGK) and PAX-5 Robert K McCall, Paula Moore, Nancy S Rosenthal, Angela G Niehaus, Bayard Powell, Mark J Pettenati Cytogenetics and Molecular Cytogenetics, Wake Forest University Medical Center, Winston-Salem, North Carolina. [email protected]
Published in Atlas Database: August 2019
Online updated version : http://AtlasGeneticsOncology.org/Reports/t0209p11p13PettenatiID100099.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70753/08-2019-t0209p11p13PettenatiID100099.pdf DOI: 10.4267/2042/70753
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Cyto-Pathology Case report on B-cell acute lymphoblastic leukemia Classification with t(2;9)(p11;p13) involving the immunoglobulin kappa locus (IGK) and PAX-5. Immunophenotype Flow cytometric analysis of the peripheral blood identified a population of blasts Clinics (80% of all cells) expressing CD45, CD10, CD19, CD20, CD34, HLA-DR, CD33 (variable), CD11b Age and sex: 30 years old male patient. (dim), cCD22, cCD79a, and nTdT. The blasts were Previous history: no preleukemia, no previous negative for CD3, CD4, CD5, CD7, CD56, sIg malignancy, no inborn condition of note kappa, sIg lambda, CD13, CD14, CD15, CD36, Organomegaly: no hepatomegal, no splenomegaly, CD64, and cMPO. enlarged lymph nodes (Tender right axillary, left Rearranged Ig Tcr: Not performed posterior cervical, and left inguinal Pathology: Acute lymphoblastic leukemia lymphadenopathy.), central nervous system Electron microscopy: Not performed involvement (Cytology revealed rare atypical mononuclear cells, favor reactive.) Diagnosis: B-lymphoblastic leukemia/lymphoma, not otherwise specified Blood Survival WBC: 17.8X 109/l Date of diagnosis: 04-2018 HB: 11.3g/dl Platelets: 38X 109/l Treatment: ECOG 1910 Blasts: 85% Complete remission was obtained Treatment related death: no Note Hypercellular marrow (>90%) with sheets of blasts on bone marrow core biopsy. Bone marrow Relapse: No relapse in the context of a short follow- aspirate smears contained 97% blasts with fine up period chromatin, single to multiple small nucleoli, and Status: Alive scant pale-blue cytoplasm. Last follow up: 05-2018
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 259 B-cell acute lymphoblastic leukemia with t(2;9)(p11;p13) McCall RK et al. involving the immunoglobulin kappa locus (IGK) and PAX-5
Survival: 1months IGK (Immunoglobulin Kappa) (2p11.2). The human IGK locus at 2p12 spans 1820 kb. It consists of 76 Karyotype IGKV genes belonging to 7 subgroups, 5 IGKJ segments, and a unique IGKC gene. Sample: Bone marrow Culture time: 24h Comments Banding: GTG Chromosomal translocations involving PAX5 are Results: 45,XY,t(2;9)(p11;p13),-20[18]/46,XY[1] known to occur in cases of B-lymphoblastic leukemia (B-ALL), often involving a range of Other Findings possible fusion gene partners (1). In addition to these Genes involved and Proteins rearrangements, many cases of B-ALL demonstrate PAX5 (paired box gene 5) (9p13.2). The PAX5 copy number variations involving PAX5 (2). coding region extends over a genomic interval of Despite these reports, only two other case of t(2;9) approximately 200kb and comprises 10 exons. Two involving fusion of PAX5 and 2p11 have been alternative transcripts have been identified, reported to date (3,4). originating from alternative promotor usage, Neither of these reports confirmed the involvement containing exon 1A or 1B. Full length mRNA is of the immunoglobulin kappa locus as demonstrated 3650 bp. PAX5 belongs to the paired box family of in the present case. transcription factors. It is involved in a multitude of We report the first case of PAX5/IgK fusion developmental processes. PAX5 was originally confirmed by FISH, suggesting a possible identified as a B-cell specific transcription factor (B- mechanism in B-ALL that mirrors other lymphomas cell-specific activator protein, BSAP). Recently, which overexpress gene products as a result of PAX5 expression has been shown not only joining with immunoglobulin heavy or light chain continuously required for B cell lineage commitment loci. during early B cell development but also for B Note from the Editor: this translocation is a variant lineage maintenance. PAX5 contains a paired box of the rare t(9;14)(p13;q32) PAX5/IGH, although (DNA binding) domain, a truncated homeo domain the t(9;14) has so far only been described in homology region, a transactivation domain, and an lymphomas. inhibitory domain.
Example of chromosome 2;9 translocation. Note: A potential dicentric 9;20 was ruled out with centromeric probes of chromosome 9 and 20. FISH showing fusion (yellow) of IgK (green) [Cyto Cell] and PAX5 (red) [Empire Genomics] on the derived chromosome 9. Note: Negative for BCR/ABL1 fusion by FISH.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 260
B-cell acute lymphoblastic leukemia with t(2;9)(p11;p13) McCall RK et al. involving the immunoglobulin kappa locus (IGK) and PAX-5
Two interphases demonstrating consistent connection of IgK (green)-PAX5 (red)-IgK (green) suggesting rearrangment/fusion of PAX5/IgK.
Bone marrow core biopsy showing extensive blast proliferation and peripheral blood (inset) demonstrating atypical blast cytomtrating atypical blast cytomorphology with occasional deep nuclear fissures.
Stasevich I, Inglott S, Austin N, Chatters S, Chalker J, Addy References D, Dryden C, Ancliff P, Ford A, Williams O, Kempski H. PAX5 alterations in genetically unclassified childhood Lu XY, Harris CP, Cooley L, Margolin J, Steuber PC, Precursor B-cell acute lymphoblastic leukaemia. Br J Sheldon M, Rao PH, Lau CC. The utility of spectral Haematol. 2015 Oct;171(2):263-272 karyotyping in the cytogenetic analysis of newly diagnosed pediatric acute lymphoblastic leukemia. Leukemia. 2002 This article should be referenced as such: Nov;16(11):2222-7 McCall RK, Moore P, Rosenthal NS, Niehaus AG, Powell Nebral K, Denk D, Attarbaschi A, König M, Mann G, Haas B, Pettenati MJ. B-cell acute lymphoblastic leukemia with OA, Strehl S. Incidence and diversity of PAX5 fusion genes t(2;9)(p11;p13) involving the immunoglobulin kappa in childhood acute lymphoblastic leukemia. Leukemia. 2009 locus (IGK) and PAX-5. Atlas Genet Cytogenet Oncol Jan;23(1):134-43 Haematol. 2020; 24(6):259-261.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 261
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Case Report Section
KMT2A-CBL Fusion Gene Resulting from del(11)(q23.3q23.3) Identified by Chromosome Microarray Analysis - second report in AML Temenuzhka Boneva and Elisabeth Nacheva HSL Analystics LLP OncoGenomics, London UK and UCL Cancer Institute, UK; [email protected] Published in Atlas Database: August 2019 Online updated version : http://AtlasGeneticsOncology.org/Reports/del11q23q23BonevaID100098.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70754/08-2019-del11q23q23BonevaID100098.pdf DOI: 10.4267/2042/70754
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Granulopoesis appears to have normal granulation. Abstract Erythropoiesis appears normoblastic and not grossly Case report on KMT2A-CBL Fusion Gene Resulting dysplastic. from del(11)(q23.3q23.3) Identified by Some of the mature neutrophils appear dysplastic Chromosome Microarray Analysis - second report in with abnormal nuclear stranding. Megakaryocytes AML are not seen. Clinics Cyto-Pathology Age and sex: 18 years old female patient. Classification Previous history: no preleukemia, no previous Phenotype AML with 'recurrent cytogenetic malignancy ; no inborn condition of note translocations' Organomegaly: no hepatomegaly, no splenomegaly Immunophenotype CD45lo/ SSClo blasts account , no enlarged lymph nodes , no central nervous for 61.2% of total BM intact single cells. Positive system involvement for: CD34, CD33, CD15, CD38, CD56, HLADR. By intracellular staining, these cells were entirely Blood cCD34+ and 45% were cMPO+. These cells were WBC: 1.3 (neut 0.1x109/L);X 109/l negative for: TdT, cCD3- and cCD79a-. HB: 7.4g/dl Rearranged Ig Tcr Not performed 9 Platelets: 55X 10 /l Pathology Not performed Note Electron microscopy Not performed The marrow smears showed heavily infiltrated with Diagnosis Common Acute Myeloid Leukaemia. medium sized cells, which are round, have minimal lightly basophilic agranular cytoplasm and inconspicuous nucleoli, with partially clumped Survival nuclear chromatin. Some of the nuclei appear Date of diagnosis 05-2017 cleaved or folded. A minority of the cells has very Treatment according to FLAG-Ida chemotherapy immature chromatin and/or prominent nucleoli, and protocol. are more classically blasts. There are no Auer rods in Complete remission: Complete remission was either population. Very minimal evidence of obtained on 06/2017 maturing granulopoiesis and erythropoiesis is seen.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 262 KMT2A-CBL Fusion Gene Resulting from Boneva T, Elisabeth Nacheva E del(11)(q23.3q23.3) Identified by Chromosome Microarray Analysis - second report in AML
Treatment related death: no protocol to look for aberrations involving 11q23.3 Relapse: no and for the presence of inv(16)/t(16;16) respectively. Status: Alive 2. Chromosome microarray analysis (CMA) was performed using 8x60K oligonucleotide arrays Last follow up: 08-2019 (Agilent) analyzed with Agilent Genomic Survival: 26 months + Workbench v 7.0 (settings: ADM2, threshold 6, 3 consecutive probes) at an average resolution of Karyotype 50Kb. The patient's DNA was hybridized against Sample Bone marrow commercially available same-sex control DNA Culture time 24h (Promega) as done before (Nacheva et al., 2013). 3. The target myeloid gene panel TruSight on a Banding GTG MiSeq platform (Illumina, USA) was used to screen Results mutational hotspots of 54 cancer-related genes 46,XX[20] - All 20 G-banded metaphase cells relevant in myeloid malignancy as before (Boneva et analysed showed a female karyotype with no al., 2017). Gene variances were reported at allele apparent cytogenetic abnormalities. frequencies (VAF) >10% and at minimum read Other molecular cytogenetics technics depth of 300 as per manufacturers criteria. We used 1. FISH analysis was performed screening for the Catalogue of Somatic Mutations In Cancer cryptic chromosome rearrangements using the (COSMIC), dbSNP and 1000 genome (>2%) to commercial dual colour break apart KMT2A (MLL) classify gene variants as either drivers, variants of and dual colour dual fusion CBFB-MYH11 probes unknown significance and/or germline (both Cytocell, Cambridge, UK) following routine polymorphisms (SNPs). Genome addresses are given according to hg19 (GRCH37)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 263
KMT2A-CBL Fusion Gene Resulting from Boneva T, Elisabeth Nacheva E del(11)(q23.3q23.3) Identified by Chromosome Microarray Analysis - second report in AML
Other molecular cytogenetics results gene leads to 5' KMT2A -3'CBL fusion as described. FISH: nuc ish11q23(5'KMT2Ax2,3'KMT2Ax1) What is the prognostic impact of this fusion gene is (5'KMT2Acon3'KMT2Ax1)[92/100], still unclear. Our patient has achieved complete 16p13.11(MYH11x2),16q22.1(CBFBx2)[100]. remission with chemotherapy for 26 months. In both Out of the 100 cells analysed, 92 showed an previous and present cases, the fusion 5' KMT2A - abnormal signal pattern for KMT2A indicative for 3'CBL gene results from a cryptic genome loss, the interstitial deletion of the 3' site of the KMT2A gene detection of which is beyond G banding resolution probe [figure 1a]. All 100 cells analysed were and leaves the chromosome 11 banding pattern negative for CBFB-MYH11 rearrangement. intact. Of a note, the KMT2A-CBL fusion was also CMA: arr[GRCh37] 11q23.3 described in T-ALL resulting form (118355060_119103310)x1 (748Kb). Whole t(11;11)(q23;q23). genome scan identified a female genome with two The presented case provides further support to the SNP polymorphic markers reported in normal investigative power of CMA and a reminder for the individuals at the Database of Genomic Variants existence of rare and possibly recurrent 5' KMT2A - (DGV; http://dgv.tcag.ca) and a 748Kb deletion 3'CBL fusion gene in adult AML. within the 11q23.3 region, commencing at chr11:118,355,060 and terminating at References chr11:119,103,310 [figure 1b-d]. The genome loss Boneva T, L. Rai, D. Brazma, R. Dunn, C. Grace, E. includes 47.855bp from the 5' part of KMT2A and Nacheva;. Prognostic Significance of gene mutations in 26.324bp from the 3' part of the CBL gene likely MDS depends on the loci of gene variances. Abstract/poster (E1176); 22-nd Congress of the European Haematology resulting in formation of a KMT2A-CBL fusion as Association, Madrid; 22-25 June, 2017 described before (Huret et al., 2013; Meyer et al., 2018). Cargo CA, Rowbotham N, Evans PA, Barrans SL, Bowen DT, Crouch S, Jack AS. Targeted sequencing identifies Variants: The only mutation identified in this patients with preclinical MDS at high risk of disease sample is a missense variance of the RUNX1 gene progression Blood 2015 Nov 19;126(21):2362-5 (NP_001745.2:p.Gly372Ser at 36164761) which is Chen B, Jiang L, Zhong ML, Li JF, Li BS, Peng LJ, Dai YT, reported SNV which is predicted to be tolerated' Cui BW, Yan TQ, Zhang WN, Weng XQ, Xie YY, Lu J, Ren (http://cancer.sanger.ac and RB, Chen SN, Hu JD, Wu DP, Chen Z, Tang JY, Huang JY, http://www.ncbi.nlm.nih. gov/SNP) and therefore Mi JQ, Chen SJ. Identification of fusion genes and considered indicative for disease only in the characterization of transcriptome features in T-cell acute lymphoblastic leukemia Proc Natl Acad Sci U S A 2018 Jan presence of cell morphology and 9;115(2):373-378 immunophenotyping evidence (Genovese et al., Fu JF, Hsu JJ, Tang TC, Shih LY. Identification of CBL, a 2014; Cargo et al., 2015 and reviewed in Steensma, proto-oncogene at 11q23 3, as a novel MLL fusion partner 2018). in a patient with de novo acute myeloid leukemia Genes Chromosomes Cancer Comments Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood The most common rearrangements of the KMT2A DNA sequence N Engl J Med 2014 Dec 25;371(26):2477- gene are reciprocal chromosome translocations and 87 their prognostic relevance is well established, but Huret, JL.. Del(11)(q23q23)/ MLL/CBL - t(11;11)(q23;q23) deletions of the same region leading to KMT2A MLL/CBL. Atlas Genet Cytogenet Oncol Haematol. fusion rearrangements are rare and little is known 2013;17(2):126-128. about their prognostic significance. Meyer C, Burmeister T, Gröger D, et al. The MLL We describe the second case of AML with extremely recombinome of acute leukemias in 2017 Leukemia 2018 rare 5'KMT2A-3'BCL fusion gene resulting from Feb;32(2):273-284 interstitial cryptic loss (748Kb) within the 11q23.3 Nacheva EP, Grace CD, Brazma D, Gancheva K, Howard- chromosome region identified by FISH and CMA Reeves J, Rai L, Gale RE, Linch DC, Hills RK, Russell N, analysis. The first case of adult AML, which was Burnett AK, Kottaridis PD. Does BCR/ABL1 positive acute myeloid leukaemia exist? Br J Haematol 2013 reported in 2003, affected a 29-year-old female May;161(4):541-50 doi: 10 patient (Fu et al., 2003; also reported in Shih et al., 2006 and in Huret, 2013). In the previous report, the Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential Blood Adv 2018 authors demonstrated that the hybrid gene Nov 27;2(22):3404-3410 (5'KMT2A-3'CBL) is the result of loss of 3'of KMT2A with breakpoint in exon 9 and fusion whit This article should be referenced as such: exon 8 of CBL gene. In present case, we used FISH Boneva T, Elisabeth Nacheva E. KMT2A-CBL Fusion and CMA to demonstrate interstitial deletion of the Gene Resulting from del(11)(q23.3q23.3) Identified by 3' region of the KMT2A gene. We therefore assume Chromosome Microarray Analysis - second report in that the loss of 3' part of KMT2A AML. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6):262-264.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(6) 264
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS Instructions to Authors
Policies- Instructions to Authors See http://documents.irevues.inist.fr/bitstream/handle/2042/48486/Instructions-to-authors.pdf Manuscripts submitted to the Atlas must be submitted solely to the Atlas. The Atlas publishes "cards", "deep insights", "case reports", and "educational items". Cards are structured review articles. Detailed instructions for these structured reviews can be found at: http://AtlasGeneticsOncology.org/Forms/Gene_Form.html for reviews on genes, http://AtlasGeneticsOncology.org/Forms/Leukaemia_Form.html for reviews on leukaemias, http://AtlasGeneticsOncology.org/Forms/SolidTumour_Form.html for reviews on solid tumours, http://AtlasGeneticsOncology.org/Forms/CancerProne_Form.html for reviews on cancer-prone diseases. According to the length of the paper, cards are divided, into "reviews" (texts exceeding 2000 words), "mini reviews" (between), and "short communications" (texts below 400 words). Deep Insights are written as traditional papers, made of paragraphs with headings, at the author's convenience. Case Reports in haematological malignancies are dedicated to recurrent –but rare- chromosomes abnormalities in leukaemias/lymphomas; see http://atlasgeneticsoncology.org//BackpageAuthors.html#CASE_REPORTS . It is mandatory to use the specific "Submissionformfor Case reports": see http://AtlasGeneticsOncology.org/Reports/Case_Report_Submission.html. Educational Items must be didactic, give full information and be accompanied with iconography. Research articlesThe Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles. Authorship All authors should qualify for authorship according to the ICMJE criteria.
Editorial Ethics see http://documents.irevues.inist.fr/bitstream/handle/2042/56068/Policies-editorial-ethics.pdf for: Peer Review Process / Commissioned papers vs Unsolicited papers /Responsibility for the reviewers / Editorial responsibilities / Conflict of interest- Competing interests/ Privacy and Confidentiality - Iconography / Protection of Human Subjects and Animals in Research / Duplicate Publication/ Plagiarism / Retracting a publication
Subscription The Atlas is FREE! Costs/Page Charge There is NO page charge. PubMed Central Once the paper online, authors are encouraged to send their manuscript to PubMed Central http://www.ncbi.nlm.nih.gov/pmc/ with reference to the original paper in the Atlas in http://documents.irevues.inist.fr/handle/2042/15655
Corporate patronage, sponsorship and advertising Enquiries should be addressed to [email protected].
Rules, Copyright Notice and Disclaimer http://documents.irevues.inist.fr/bitstream/handle/2042/48487/Copyright-sponsorship.pdf Property As "cards" are to evolve with further improvements and updates from various contributors, the property of the cards belongs to the editor, and modifications will be made without authorization from the previous contributor (who may, nonetheless, be asked for refereeing); contributors are listed in an edit history manner. Authors keep the rights to use further the content of their papers published in the Atlas, provided that the source is cited. Copyright The information in the Atlas of Genetics and Cytogenetics in Oncology and Haematology is issued for general distribution. All rights are reserved. The information presented is protected under international conventions and under national laws on copyright and neighbouring rights. Commercial use is totally forbidden. Information extracted from the Atlas may be reviewed, reproduced or translated for research or private study but not for sale or for use in conjunction with commercial purposes. Any use of information from the Atlas should be accompanied by an acknowledgment of the Atlas as the source, citing the uniform resource locator (URL) of the article and/or the article reference, according to the Vancouver convention. Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favouring. The views and opinions of contributors and authors expressed herein do not necessarily state or reflect those of the Atlas editorial staff or of the web site holder, and shall not be used for advertising or product endorsement purposes. The Atlas does not make any warranty, express or implied, including the warranties of merchantability and fitness for a particular purpose, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, and shall not be liable whatsoever for any damages incurred as a result of its use. In particular, information presented in the Atlas is only for research purpose, and shall not be used for diagnosis or treatment purposes. No responsibility is assumed for any injury and/or damage to persons or property for any use or operation of any methods products, instructions or ideas contained in the material herein. See also "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication - Updated October 2004": http://www.icmje.org. http://AtlasGeneticsOncology.org © ATLAS - ISSN 1768-3262 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS