Number 3 March 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Volume 1 - Number 1 May - September 1997

Volume 20 - Number 3 March 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematologyis 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, Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France phone +33 5 49 44 45 46 [email protected] or [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

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 Editor-in-Chief Jean-Loup Huret (Poitiers, France)

Board Members Sreeparna Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Banerjee Alessandro Department of Health Sciences, University of Milan, Italy; [email protected] Beghini Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; Antonio Cuneo [email protected] Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Paola Dal Cin [email protected] François IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Desangles Dewoitine C212, 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, Enric Domingo OX37BN, UK [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, Kessel 6500 HB Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Oskar A. Haas Children's Cancer Research Institute Vienna, Vienna, Austria. [email protected] Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; Anne Hagemeijer [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, Nyla Heerema USA; [email protected] Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; Sakari Knuutila [email protected] Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; Lidia Larizza l.larizza@auxologico Roderick Mc Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Leod Cultures, Braunschweig, Germany; [email protected] Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; Cristina Mecucci [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; miller.konstantin@mh- Konstantin Miller hannover.de 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 Stefan Nagel Cultures, Braunschweig, Germany; [email protected] Florence Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; Pedeutour [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Susana Raimondi Memphis, Tennessee 38105-3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; Sabine Strehl [email protected] Nancy Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; Uhrhammer [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Roberta Vanni Italy; [email protected] Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Franck Viguié Universitaire Necker-Enfants Malades, 75015 Paris, France; [email protected]

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’InformationScientifique 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

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Volume 20, Number 3, March 2016 Table of contents

Gene Section

ANKHD1 (ankyrin repeat and KH domain containing 1) 98 Joao Agostinho Machado-Neto, Fabiola Traina CASP8AP2 (caspase 8 associated protein 2) 102 Rocío Juárez-Velázquez, Patricia Pérez-Vera TRIB1 (tribbles pseudokinase 1) 106 Jessica Johnston, Endre Kiss-Toth DOCK1 (Dedicator of cytokinesis 1) 115 Ping Li, Fung Zhao, Annie N. Cheung NR3C1 (nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor) 121 Thomas D. Siamatras, Constantine A. Stratakis CCND1 (B-cell leukemia/lymphoma 1) 130 Leukaemia Section

Classification of myelodysplastic syndromes 2015 155 Virginie Eclache t(11;19)(q13;p13) FSTL3/CCND1 162 Jean-Loup Huret

Case Report Section

Atlas Genet Cytogenet Oncol Haematol. 1998; 2(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

ANKHD1 (ankyrin repeat and KH domain containing 1) Joao Agostinho Machado-Neto, Fabiola Traina Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas (JAMN, FT), Department of Internal Medicine, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto (FT), Sao Paulo, Brazil. [email protected]; [email protected]

Published in Atlas Database: March 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/ANKHD1ID46476ch5q31.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62521/03-2015-ANKHD1ID46476ch5q31.pdf DOI: 10.4267/2042/62521 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

plus strand; 34 exons; mRNA: 8233 bp) is the Abstract longest transcript and encodes the isoform 1 (2542 ANKHD1 is differentially expressed in human aa protein). The transcript variant 2 (start: cancers, and potentially regulates multiple cellular 139781399 and end: 139852062 bp; orientation: plus functions and participates as a scaffold for protein- strand; 11 exons; mRNA: 2161 bp) uses an alternate protein interactions through its ankyrin-repeat in-frame splice site in the 5` coding region, lacks domains. Recently, studies have indicated that several exons, uses an alternate 3` terminal exon and ANKHD1 is involved in the regulation of important encodes the isoform 2, which is shorter and presents biological process that participate in the malignant a distinct C-terminus compared to isoform 1 (616 aa phenotype, including cell cycle progression, protein). Transcript variant 3 (start: 139781399 and proliferation, clonogenicity and migration. The end: 139852062 bp; orientation: plus strand; 11 present review on ANKHD1 contains data on exons; mRNA: 2194 bp) lacks several exons, uses an DNA/RNA, protein encoded and where the gene is alternate 3` terminal exon and encodes the isoform 3 implicated. that also has a distinct C-terminus compared to Keywords isoform 1 (627 aa protein). Transcrit variant 4 (start: ANKHD1; Cell cycle; Cell proliferation; Migration; 139781399 and end: 139852062 bp; orientation: plus Cancer strand; 10 exons, mRNA: 2084 bp) also lacks several exons, uses an alternate 3` terminal exon, encodes Identity the isoform 4 that has a distinct C-terminus compared to isoform 1 and is the shortest of all Other names: MASK, VBARP, PP2500 isoforms (581 aa protein). Additionally, ANKHD1- HGNC (Hugo): ANKHD1 EIF4EBP3 is a readthrough transcript involving Location: 5q31.3 ANKHD1 and EIF4EBP3 genes, which encodes a protein that contains multiple ankyrin repeats, single DNA/RNA KH-domain and a C-terminus with a portion from the EIF4EBP3 gene (start: 139781399 and end: Description 139929163 bp; orientation: plus strand; 36 exons, The entire ANKHD1 gene is about 147 Kb (start: mRNA: 8349 bp; protein: 2617 aa). Data searched at 139781399 and end: 139929163 bp; orientation: plus GenBank NCBI strand). The ANKHD1 gene encodes for 4 transcript (http://www.ncbi.nlm.nih.gov/genbank/) and UCSC variants. The transcript variant 1 (start: 139781399 Genome Browser (https://genome.ucsc.edu/). and end: 139919441 bp; orientation:

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3) 98 ANKHD1 (ankyrin repeat and KH domain containing 1) Machado-Neto JA, Traina F

this protein integrates multiple signaling pathways Protein and participates as scaffold for protein-protein Description interactions (Jernigan and Bordenstein, 2015). A large part of the knowledge regarding the functions The ANKHD1 protein has 4 isoforms. Isoforms 2, 3 of ANKHD1 was obtained by experiments using its and 4 are smaller and less characterized than isoform orthologous protein Mask (multiple ankyrin repeats 1. Isoform 1 of ANKHD1 protein consists of 2542 single KH domain). In Drosophila, Mask acts in the amino acids with a molecular weight of 270 kDa, has signal transduction pathway mediated by Cws 20 ankyrin repeats distributed in two blocks and a K (Corkscrew; orthologous of SHP2) (Smith, et al., homology (KH) domain in the C-terminal region. 2002), participates in the Hippo signaling pathway The schematic representation of ANKHD1 protein activation through its association with Yki (Yorkie, (isoform 1) is illustrated in Figure 1. orthologous of YAP1) (Sidor, et al., 2013, Sansores- Expression Garcia, et al., 2013) and potentially regulates Hop Ubiquitous. signaling pathway (Hopscotch, orthologous of JAK) (Muller, et al., 2005). Localisation In humans, ANKHD1 associates with SHP2, ANKHD1 is predominantly found in the cytoplasm however the biologic consequence of this protein (Figure 2). interaction remains indeterminate (Traina, et al., 2006). ANKHD1 and YAP1 interaction has also Function been confirmed in human cells (HEK293 and The ANKHD1 protein contains 20 ankyrin repeats, DU145 cells) and modulates the Hippo signaling which are highly conserved structures. The presence pathway activation, proliferation and cell cycle of ankyrin repeats domains suggests that progression (Sidor, et al., 2013, Sansores-Garcia, et al., 2013, Machado-Neto, et al., 2014).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3) 99 ANKHD1 (ankyrin repeat and KH domain containing 1) Machado-Neto JA, Traina F

ANKHD1 interacts with SIVA and modulates the 58 substitution synonymous, 1 insertion frameshift microtubule dynamics, cell proliferation and and 1 deletion frameshift mutations are reported in migration of human leukemia cells (Machado-Neto, COSMIC (Catalogue of somatic mutations in cancer; et al., 2015). In addition, ANKHD1 modulates p21 http://cancer.sanger.ac.uk/cancergenome/projects/c (CDKN1A) expression and cell cycle progression in osmic). multiple myeloma cells (Dhyani, et al., 2015, Dhyani, et al., 2012). In NT2 cells, inhibition of the Implicated in small isoform of ANKHD1 that lacks the KH domain (also designed as VBARP; isoform 3) Leukemia triggered caspase-3/7 activation (Miles, et al., 2005), Note however no similar effect on apoptosis was observed ANKHD1 was reported as highly expressed in in the other cell lines inhibited for all other leukemia cell lines and in primary bone marrow ANKHD1 isoforms (Machado-Neto, et al., 2014, samples from patients with acute myeloid leukemia Machado-Neto, et al., 2015, Dhyani, et al., 2012). A and acute lymphoid leukemia (Traina, et al., 2006). potential model for ANKHD1 cellular functions and Interestingly, ANKHD1 silencing reduced cell protein interactions is summarized in Figure 3. proliferation, clonogenicity, migration and Homology tumorigenesis of leukemia cells (Machado-Neto, et al., 2015). ANKHD1 shares high homology with ANKRD17 (ankyrin repeat domain 17), both orthologous Multiple myeloma proteins to Mask protein from Drosophila. Disease ANKHD1 also shares high homology among Multiple myeloma cell lines and primary plasma different species (Table 1). cells from myeloma multiple patients presented a high expression of ANKHD1 (Dhyani, et al., 2012). Mutations In multiple myeloma cell lines, ANKHD1 inhibition resulted in a delay in cell cycle progression and Somatic lower cell proliferation, clonal growth, migration Recurrent mutations in the ANKHD1 gene are rare, and tumor formation (Dhyani, et al., 2015, Dhyani, 180 substitution missense, 13 substitution nonsense, et al., 2012).

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ANKHD1 (ankyrin repeat and KH domain containing 1) Machado-Neto JA, Traina F

Prostate cancer Tsai PC, Shen CK, Yan YT. Ankrd17, an ubiquitously expressed ankyrin factor, is essential for the vascular Note integrity during embryogenesis. FEBS Lett. 2009 Sep High expression of ANKHD1 was observed in 3;583(17):2765-71 prostate cancer cell lines (Machado-Neto, et al., Jernigan KK, Bordenstein SR. Tandem-repeat protein 2014). Using the siRNA approach, ANKHD1 domains across the tree of life. PeerJ. 2015;3:e732 silencing reduced proliferation, tumor formation, Müller P, Kuttenkeuler D, Gesellchen V, Zeidler MP, and cell cycle progression in prostate cancer cells Boutros M. Identification of JAK/STAT signalling (Machado-Neto, et al., 2014). components by genome-wide RNA interference. Nature. 2005 Aug 11;436(7052):871-5 Breast cancer Machado-Neto JA, Lazarini M, Favaro P, de Melo Campos Prognosis P, Scopim-Ribeiro R, Franchi Junior GC, Nowill AE, Lima In two independent cohorts of breast cancer patients, PR, Costa FF, Benichou S, Olalla Saad ST, Traina F. ANKHD1 silencing inhibits Stathmin 1 activity, cell high expression of ANKHD1 was associated with proliferation and migration of leukemia cells. Biochim worsened outcomes (Sansores-Garcia, et al., 2013). Biophys Acta. 2015 Mar;1853(3):583-93 Miles MC, Janket ML, Wheeler ED, Chattopadhyay A, To be noted Majumder B, Dericco J, Schafer EA, Ayyavoo V. Molecular and functional characterization of a novel splice variant of Although ANKHD1 presents high homology with ANKHD1 that lacks the KH domain and its role in cell ANKRD17 (both orthologous proteins of Mask), the survival and apoptosis. FEBS J. 2005 Aug;272(16):4091- Ankrd17 knockout mice presents embryonic 102 lethality (Hou, et al., 2009), indicating that these Sansores-Garcia L, Atkins M, Moya IM, Shahmoradgoli M, proteins do not play redundant functions. Another Tao C, Mills GB, Halder G. Mask is required for the activity interesting point is that, accordingly to current data, of the Hippo pathway effector Yki/YAP. Curr Biol. 2013 Feb 4;23(3):229-35 ANKHD1 participates in cell proliferation and cell cycle progression in different neoplastic cells; Sidor CM, Brain R, Thompson BJ. Mask proteins are cofactors of Yorkie/YAP in the Hippo pathway. Curr Biol. however the ANKHD1-interacting proteins appear 2013 Feb 4;23(3):223-8 to vary, depending on the cellular context. Smith RK, Carroll PM, Allard JD, Simon MA. MASK, a large ankyrin repeat and KH domain-containing protein involved References in Drosophila receptor tyrosine kinase signaling. Development. 2002 Jan;129(1):71-82 Dhyani A, Duarte AS, Machado-Neto JA, Favaro P, Ortega MM, Olalla Saad ST. ANKHD1 regulates cell cycle Traina F, Favaro PM, Medina Sde S, Duarte Ada S, progression and proliferation in multiple myeloma cells. Winnischofer SM, Costa FF, Saad ST. ANKHD1, ankyrin FEBS Lett. 2012 Dec 14;586(24):4311-8 repeat and KH domain containing 1, is overexpressed in acute leukemias and is associated with SHP2 in K562 cells. Dhyani A, Machado-Neto JA, Favaro P, Saad ST. ANKHD1 Biochim Biophys Acta. 2006 Sep;1762(9):828-34 represses p21 (WAF1/CIP1) promoter and promotes multiple myeloma cell growth. Eur J Cancer. 2015 This article should be referenced as such: Jan;51(2):252-9 Machado-Neto JA, Traina F. ANKHD1 (ankyrin repeat Hou SC, Chan LW, Chou YC, Su CY, Chen X, Shih YL, and KH domain containing 1). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3):98-101.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3) 101 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

CASP8AP2 (caspase 8 associated protein 2) Rocío Juárez-Velázquez, Patricia Pérez-Vera Laboratorio de Cultivo de Tejidos, Departamento de Genética Humana, Instituto Nacional de Pediatria, Mexico, Mexico; [email protected]

Published in Atlas Database: March 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/CASP8AP2ID926ch6q15.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62522/03-2015-CASP8AP2ID926ch6q15.pdf DOI: 10.4267/2042/62522 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

multiple transcript variants encoding the same Abstract protein. CASP8AP2 was initially identified as a pro- Protein apoptotic protein that transmits an apoptosis indication through the death-inducing signaling Description complex. Size 1982 amino acids; 222,658 kDa protein. More recently, diverse functions have been It contains a motif structurally related to described including TNF-induced NF-kappaB CED4/Apaf1 (602233) and a C-terminal death activation, cell-cycle progression and cell division, effector domain (DED)-recruiting domain (DRD); a regulation of histone gene transcription and histone NCOA2-binding domain (position 1709-1982aa); a mRNA processing. SUMO interaction motifs: SIM1 (position 1683- Keywords 1687aa), SIM2 (position 1737-1741aa, SIM3 CASP8AP2 (position 1794-1798aa) which mediate the binding to polysumoylated substrates. Identity The FLASH activity is regulated by sumoylation (Alm-Kristiansen et al., 2009). Other names: FLASH, CED-4, FLJ11208, KIAA1315, RIP25 Localisation HGNC (Hugo): CASP8AP2 Nucleus, cytoplasm, mitochondrion. Location Function 6q15 ; CASP8AP2 gene is located on the long arm Component of the apoptosis signaling pathway of chromosome 6 NC_000006.12, in opposite required for the activation of CASP8 in Fas- orientation mediated apoptosis (Imai Y et al., 1999). Component of the machinery required for histone DNA/RNA precursor mRNA expression and essential for 3end maturation of histone mRNAs (Barcaroli D et al., Description 2006; De Cola et al., 2012; Yang XC et al., 2009). 44,537 bp; 10 exons It participates in TNF-alpha-induced blockade of glucocorticoid receptor transactivation at the nuclear Transcription receptor coactivator level, upstream and Three transcripts reported at NCBI: Variant1, independently of NF-kappa-B (Kino and Chrousos, 6,821bp NM_012115.3; Variant2, 6,782bp 2003). It also contributes to cell cycle progression at NM_001137667.1; Variant3, 6,649bp S phase (Kiriyama et al., 2009; Barcaroli D et al., NM_001137668.1. Alternative splicing results in 2006).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3) 102 CASP8AP2 (caspase 8 associated protein 2) Juárez-Velázquez R, Pérez-Vera P

Genomic location and gene products of CASP8AP2. The gene is located at 6q15, it has three transcripts, and all of them encode the same protein.

Homology Prognosis Caenorhabditis elegans protein CED-4; Mus The clinical significance of CASP8AP2 was first musculus protein FLASH reported by (Flotho C et al., 2006), the differences in its expression levels were significantly associated Implicated in with early response to treatment and the presence of minimal residual disease (MRD). CASP8AP2 t(6;11)(q15;q23) expression was analyzed in 99 children with acute Disease lymphoblastic leukemia (ALL) enrolled in the St. Acute myeloid leukemia. A t(6;11)(q15;q23) in a 50- Jude Total Therapy Study XIII protocol. Patients year-old Korean woman with acute myeloid with low levels of expression presented a lower leukemia has been reported (Park TS et al., 2009). event-free survival and higher incidence of relapse, in contrast to patients with higher expression levels. Hybrid/Mutated gene High expression was associated with greater A MLL/CASP8AP2 fusion was identified by LDI- propensity of leukemic cells to undergo apoptosis. In PCR and sequencing, a rearrangement between MLL this study CASP8AP2 was considered as an (intron 8) and CASP8AP2 (intron 7) was detected at independent prognostic marker for relapse (Flotho C the genomic DNA level. The breakpoint analysis at et al., 2006). the transcription level was not performed due to lack The usefulness of CASP8AP2 expression as a of a cDNA specimen potential marker of response to treatment has been Oncogenesis analyzed in leukemic patients from different MLL/CASP8AP2 seems to be related to poor populations. In a cohort of 39 newly diagnosed ALL clinical outcome, however, further studies are children treated with the Beijing Children`s Hospital needed to evaluate prognosis. (BCH)-ALL 2003 protocol, the bone marrow expression of CASP8AP2 at diagnosis resulted a Acute lymphoblastic leukemia suitable indicator of relapse. In the same study, CASP8AP2 low expression another cohort of 106 patients enrolled in the

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Chinese Childrens Leukemia Group (CCLG)-ALL The lower expression of CASP8AP2 has been also 2008 protocol were also analyzed, patients with low associated to deletions at band 6q15-q16.1, which CASP8AP2 expression showed higher relapse rates, are often detected in patients with T-ALL (Remke M lower relapse-free survival and lower overall- et al., 2009). These deletions result in down survival, in comparison to the higher-expression regulation of the gene and poor early response to group (Jiao Y et al., 2012). ). treatment. In 73 T-cell ALL samples obtained from In an independent study a gene signature of 14 genes, patients enrolled in the multicenter ALL-BFM 1990, including CASP8AP2 and H2AFZ, was identified ALL-BFM 1995 and ALL-BFM 2000 protocols, (Flotho C et al., 2007); their low expressions were deletion 6q15-q16.1 was associated with associated to relapse. Based on this result, the unfavorable MRD levels. Although deletion 6q15- expressions of CASP8AP2 and H2AFZ were q16.1 involves several genes, CASP8AP2 was the analyzed in a cohort of 88 ALL Mexican children single one with a better association between the treated with the Popular Medical Insurance protocols deletion and the less efficient induction of apoptosis (Juárez-Velázquez R et al., 2014). An increased risk by chemotherapy (Remke M et al., 2009). for early relapse in patients with low expression of Cytogenetics CASP8AP2 was found, confirming its usefulness as The del(6)(q15-q16.1)comprises 2.54 Mb. a risk marker; the H2AFZ expression did not showed the same effect. The CASP8AP2 expression was not Diffuse large B-cell lymphomas )( an independent marker of relapse, but combined activated B-cell like subtype) characteristics as the low expressions of both genes Loss of CASP8AP2 in 35% of cases. Imbalance with and high white blood cell count, identified more possible pathogenic relevance (Scholtysik R et al., accurately patients at greater risk of relapse (Juárez- 2015). Velázquez R et al., 2014). Although the prognostic value of CASP8AP2 expression as an independent factor is controversial (Yang YL et al., 2010), References combined with expressions of other genes such as . H2AFZ (Juárez-Velázquez R et al., 2014) and ARS2 Alm-Kristiansen AH, Norman IL, Matre V, Gabrielsen OS.. (Cui L et al., 2015), could more precisely predict SUMO modification regulates the transcriptional activity of high risk of relapse in ALL. ). FLASH. Biochem Biophys Res Commun 2009; 387 (3): 494- Epigenetic modifications are also related to the 499 down-regulation of CASP8AP2. DNA Barcaroli D, Bongiorno-Borbone L, Terrinoni A, Hofmann hypermethylation of the gene promoter was analyzed TG, Rossi M, Knight RA, Matera AG, Melino G, De Laurenzi in 86 children with ALL, treated according to the V.. FLASH Is Required for Histone Transcription and S- Phase Progression Proc Natl Acad Sci U S A 2006; 103 BCH-2003 and CCLG-2008 protocols. The (40): 14808-14812 percentage of methylation of two CpG sites at positions -1189 and -1176 were inversely correlated Cui L, Gao C, Zhang RD, Jiao Y, Li WJ, Zhao XX, Liu SG, Yue ZX, Zheng HY, Deng GR, Wu MY, Li ZG, Jia HT.. Low with mRNA expression. The patients with higher Expressions of ARS2 and CASP8AP2 Predict Relapse and methylation presented MRD and poor treatment Poor Prognosis in Pediatric Acute Lymphoblastic Leukemia outcome. The results suggested that combination of Patients Treated on China CCLG-ALL 2008 Protocol Leuk methylation level and MRD might improve current Res 2015; 39 (2): 115-123 risk stratification (Li ZG et al., 2013). In regard to De Cola A, Bongiorno-Borbone L, Bianchi E, Barcaroli D, these findings, it has been demonstrated that Carletti E, Knight RA, Di Ilio C, Melino G, Sette C, De Laurenzi v.. FLASH Is Essential during Early methylation of the CASP8AP2 promoter in somatic Embryogenesis and Cooperates with p73 to Regulate stem cells and cancer cells increase their resistance Histone Gene Transcription Oncogene 2012; 31 (5): 573- to drugs (Lee KD et al., 2012). These data associate 582 this epigenetic modification with the development of Flotho C, Coustan-Smith E, Pei D,Cheng C, Song G, Pui drug resistance. CH, Downing JR, Campana D.. A Set of Genes That Regulate Cell Proliferation Predicts Treatment Outcome in T-cell acute lymphoblastic leukemia) Childhood Acute Lymphoblastic Leukemia Blood 2007; 110 (T-ALL) (4): 1271-1277 A del(6)(q15-q16.1) has been reported in Imai Y, Kimura T, Murakami A, Yajima N, Sakamaki K, approximately 12% of T-ALL patients. This Yonehara S.. The CED-4-Homologous Protein FLASH Is Involved in Fas-Mediated Activation of Caspase-8 during deletion includes the CASP8AP2 gene, whose Apoptosis Nature 1999; 398 (6730): 777-785 mRNA expression was the single most down- Jiao Y, Cui L, Gao C, Li W, Zhao X, Liu S, Wu M, Deng G, regulated gene of all 7 genes located in the deleted Li Z.. CASP8AP2 Is a Promising Prognostic Indicator in region. Pediatric Acute Lymphoblastic Leukemia Leuk Res 2012; Prognosis 36 (1): 67-71 Juárez-Velázquez R, Reyes-León A, Salas-Labadèa C, Rivera-Luna R, Velasco-Hidalgo L, López-Hernández G,

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López-Santiago N, Paredes-Aguilera R, Domènguez-López Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A, A, Bernáldez R, Pérez-Vera P.. Significance of CASP8AP2 Werft W, Breit S, Liu S, Engel F, Wittmann A, Zimmermann and H2AFZ Expression in Survival and Risk of Relapse in M, Stanulla M, Schrappe M, Ludwig WD, Bartram CR, Children with Acute Lymphoblastic Leukemia Leuk Radlwimmer B, Muckenthaler MU, Lichter P, Kulozik AE.. Lymphoma 2014; 55 (10): 2305-2311 High-Resolution Genomic Profiling of Childhood T-ALL Reveals Frequent Copy-Number Alterations Affecting the Kino T, Chrousos GP.. Tumor Necrosis Factor Alpha TGF-Beta and PI3K-AKT Pathways and Deletions at 6q15- Receptor- and Fas-Associated FLASH Inhibit 16.1 as a Genomic Marker for Unfavorable Early Treatment Transcriptional Activity of the Glucocorticoid Receptor by Response Blood 2009; 114 (5): 1053-1062 Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators J Biol Chem 2003 ; 278 (5): Scholtysik R, Kreuz M, Hummel M, Rosolowski M, 3023-3029 Szczepanowski M, Klapper W, Loeffler M, Trümper L, Siebert R, Küppers R; Molecular Mechanisms in Malignant Kiriyama M, Kobayashi Y, Saito M, Ishikawa F, Yonehara Lymphomas Network Project of the Deutsche Krebshilfe.. S.. Interaction of FLASH with Arsenite Resistance Protein 2 Characterization of genomic imbalances in diffuse large B- Is Involved in Cell Cycle Progression at S Phase Mol Cell cell lymphoma by detailed SNP-chip analysis Int J Cancer Biol 2009; 29 (17): 4729-4741 2015; 136(5): 1033-1042. Lee KD, Pai MY, Hsu CC, Chen CC, Chen YL, Chu PY, Lee Yang XC, Burch BD, Yan Y, Marzluff WF, Dominski Z.. CH, Chen LT, Chang JY,Huang TH, Hsiao SH, Leu YW.. FLASH, a Proapoptotic Protein Involved in Activation of Targeted Casp8AP2 Methylation Increases Drug Caspase-8, Is Essential for 3' End Processing of Histone Resistance in Mesenchymal Stem Cells and Cancer Cells Pre-mRNAs Mol Cell 2009; 36 (2): 267-278 Biochem Biophys Res Commun 2012; 422 (4): 578-585 Yang YL, Lin SR, Chen JS, Lin SW, Yu SL, Chen HY, Yen Li ZG, Jiao Y, Li WJ, Deng GR, Cui L, Gao C, Zhao XX, Wu CT, Lin CY, Lin JF, Lin KH, Jou ST, Hu CY, Chang SK, Lu MY, Jia HT.. Hypermethylation of Two CpG Sites Upstream MY, Chang HH, Chang WH, Lin KS, Lin DT.. Expression of CASP8AP2 Promoter Influences Gene Expression and and Prognostic Significance of the Apoptotic Genes Treatment Outcome in Childhood Acute Lymphoblastic BCL2L13, Livin, and CASP8AP2 in Childhood Acute Leukemia Leuk Res 2013; 37 (10): 1287-1293 Lymphoblastic Leukemia Leuk Res 2010; 34 (1): 18-23 Park TS, Lee SG, Song J, Lee KA, Kim J, Choi JR, Lee ST, Marschalek R, Meyer C.. CASP8AP2 Is a Novel Partner This article should be referenced as such: Gene of MLL Rearrangement with t(6;11)(q15;q23) in Acute Juárez-Velázquez R, Pérez-Vera P. CASP8AP2 Myeloid Leukemia Cancer Genet Cytogenet 2009; (caspase 8 associated protein 2). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3):102-105.

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TRIB1 (tribbles pseudokinase 1) Jessica Johnston, Endre Kiss-Toth Department of Cardiovascular Science, University of Sheffield, Sheffield, Beech Hill Road, Sheffield S10 2RX, United Kingdom Published in Atlas Database: March 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/TRIB1ID43539ch8q24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62523/03-2015-TRIB1ID43539ch8q24.pdf DOI: 10.4267/2042/62523 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

imaginal disc cells blocked the cell cycle at G2 Abstract resulting in abnormal wing morphology (Mata, et al 2000). Since then three highly conserved Review on TRIB1, with data on DNA, on the protein mammalian homologues have been indentified; encoded, and where the gene is implicated. Trib1, Trib2 and Trib3. Keywords TRIB1 DNA/RNA Identity Transcription There are two protein coding transcripts of TRIB1; Other names: C8FW, GIG-2, GIG2, SKIP1 TRIB1-001 and TRIB1-002. HGNC (Hugo): TRIB1 TRIB1-001 (Isoform 1); Transcript size: 3,635bp; Location Exon count: 3. 8q24.13; Transcript (including UTRs) TRIB1-002 (Isoform 2); Transcript size: 1,332 bp; chr8:126,442,563-126,450,644 Coding region: Exon count: 2 chr8:126,443,145-126,448,713. Note Protein The tribbles family of genes encode a group of Note highly conserved pseudokinase proteins, which are TRIB1-001: 372 amino acids; TRIB1-002: 206 thought to act as adaptors in several signalling amino acids pathways that are intimately involved in the regulation of a number of key cellular processes, Description including MAPK, and PI3K pathways. Tribbles have TRIB1 contain a N terminal (NT) domain of 60-80 also been shown to interact with ubiquitin ligases, residues and a C-terminal domain of 35-40 residues thereby promoting degradation of target proteins. and a characteristic single central Ser/Thr kinase-like Tribbles have been implicated in a number of (pseudokinase) domain. TRIB1 contains features diseases including leukaemia, metabolic syndromes consistent with its emerging role as a protein adaptor and cardiovascular disease. in signalling pathways. Tribbles proteins were first discovered in Drosophila N-Terminal Domain The NT fragment of TRIB1 as a negative regulator of string/cdc25, where when is proline and serine rich, mostly in the sequence over-expressed directly inhibited mitosis (Grosshans adjacent to the kinase-like domain. The abundance and Wieschaus 2000). Simultaneously, TRIBs were of these amino acids are a characteristic of PEST found to promote the degradation of string via the proteins that are involved in controlling the half life proteasome pathway and showed that of proteins by altering their susceptibility to overexpression of tribbles in degradation.

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There are two validated transcripts of TRIB1 (NM_025195 and NM_001282985) coding for isoforms 1 and 2 respectively. Isoform 2 has a shorter 5'UTR (untranslated region) and 5' coding region compared to isoform 1 and initiates translation further downstream. UTRs and exons are represented by the red and grey boxes respectively. Image drawn by FancyGene (Rambaldi and Ciccarelli 2009).

Other functions of these types of proteins include the associates with BGR1, which interacts with the anchoring of SH3 or WW domains of other proteins Drosophila homologue of Slbo, C/EBP transcription or acting as a substrate for proline dependent factors (Beausoleil, et al 2004, Kadam, et al 2000). phosphorylation. TRIB1 contains possible C/EBP transcription factors have been shown to phosphorylation sites for proline-dependent kinases functionally and physically interact with TRIB1 (Hegedus, et al 2007). promoting their degradation (Yoshida, et al 2013). TRIB1 also contains two evolutionary conserved Kinase-like domain TRIB1 contains a Ser/Thr motifs. The first consists of a putative nuclear kinase-like domain that is composed of some of the localisation signal, [K/R]2X2[D/E]X[D/E]. motifs present in catalytically active kinases such as The second motif contains a G-S-P consensus a Lysine crucial for ATP binding whilst others are pattern found close to the kinase-like domain. The missing. Despite this evidence would suggest TRIB1 G-S-P motif is present in human SNIP1 (Smad no to possess kinase activity. nuclear interacting protein) which functionally

Protein structure of Tribbles 1: TRIB1 has a N terminal, pseudokinase and C terminal domains. It contains four protein motifs; a putative PEST sequence, a kinase dead catalytic loop, a MEK1 binding and COP1 binding motif. The characteristic amino acid sequence for each motif is shown along with location.

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The tissue specific expression of human TRIB1 mRNA is shown. Data and figure taken from BioGPS. Additional microarray expression data from the Human Gene Expression Atlas from the Genomics Institute of the Novartis Research Foundation (GNF) can be found on the UCSC browser ( http://genome.ucsc.edu/) (Su, et al 2004, Wu, et al 2009).

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However this domain is highly conserved during activation and are dependent on levels of TRIB evolution suggesting it is important for the role of expression (Kiss-Toth, et al 2004, Sung, et al 2007). TRIB1(Hegedus, et al 2007). MEK1 phosphorylates ERK which in turn promotes C-Terminal Domain The CT domain is around 35- cell proliferation and suppression of apoptosis. The 45 amino acids long and is rich in charged amino interaction between TRIB1 (via ILLHPWF motif) acids important for protein interactions. Two and MEK1 important motifs have been identified in the CT enhances ERK phosphorylation as mutants lacking domain; a hexapeptide motif [D/E]QXVP[D/E] as a the motif were unable to do so (Yokoyama, et al COP1 (E3 ubiqutin ligase) binding site, essential for 2010) . proteasome mediated degradation of C/EBPα family TRIB1 also interacts with MKK4, a JNK activator members and a MEK 1 binding site (ILLHPWF) and implicated in the migration and proliferation of (Hegedus, et al 2007). smooth muscle and involved in the pathogenesis of Post translational modifications Several post atherosclerosis. The nuclear localisation of TRIB1- translational modifications of TRIB1 have been MKK4 complex is dependent on the NT domain of reported and validated by mass spectrometry and TRIB1, however the central kinase-like domain of listed in the PhosphoSitePlus database (Hornbeck, et TRIB1 is sufficient for its interaction with MKK4 al 2012). but the interaction is no longer preferentially nuclear Expression (Sung, et al 2007). COP1 AND C/EBPalpha TRIB1 contains a COP1 TRIB1 expression is ubiquitious with highest binding site at the carboxy terminus. COP1 is an E3 expression in the thyroid and myeloid cells (Figure). ubiquitin ligase that promotes the transfer of TRIB1 is thought to expressed in a cell-type specific ubiquitin to target substrates for degradation via the manner (Sung, et al 2006). proteasome. One of the prinicipal targets of COP1 Localisation are the family of transcription proteins CCAT/enhancer binding proteins (C/EBPs). It is Numerous over-expression experiments have shown thought TRIB1 acts to negatively regulate C/EBP TRIB1 to be located in the nucleus. It contains a proteins by acting as adaptors to recruit COP1 to putative nuclear localisation signal (Yokoyama, et al C/EBP family members thereby promoting 2010). ubiquitination and degradation. Studies have shown Function that COP1 requires TRIB1 for its action of C/EBPα TRIB1 has been shown to interact with a number of (Yoshida, et al 2013). proteins as detailed herein (Table1): MEK-1 and MKK4 Co-immunoprecipitation Homology experiments have shown specific interactions with TRIB1 homologues have been indentified in MEK1 (an ERK activator MAPKK) and MKK4 (a different species including mouse, frog and JNK activator MAPKK). Interactions with Tribbles zebrafish. Table 2 illustrates some of the TRIB1 control the extent and specificity of MAPK homologues.

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Table 2: protein and DNA identity of human TRIB1 vs other species. Data taken from Homologene and NCBI.

consequence that is based on the probability that the Mutations amino acid change is tolerable. A score closer to 0 is Note more likely to be deleterious. A score of <0.05 are A somatic point mutation of TRIB1 has been deleterious and all others are 'tolerated'. PolyPhen reported in Down syndrome (DS)- related acute predicts the effect of an amino acid substitution on megakaryocytic leukaemia (AMKL) (Yokoyama, et the structure and function of a protein using al 2012). A G:T point mutation was found in the sequence homology. A PolyPhen score represent the pseudokinase domain resulting in an amino acid probability that a substitution is damaging, scores change from arginine to leucine (R107L). When the nearer to 1 are more confidently to be predicted to be mutation was expressed in mouse bone marrow cells deleterious (opposite to SIFT score). Each score is and transferred into lethally irradiated recipient mice colour coded according to damage (SIFT; Red= there was a more rapid development of AML and deleterious, Green= tolerated. PolyPhen; Red= enhancement of ERK phosporylation suggesting a probably damaging, Orange= possibly damaging, gain of function mutation. Yokoyama, et al (2012) Green= benign) (Adzhubei, et al 2010, Gonzalez- suggests that the mutation of TRIB1 is an early event Perez and Lopez-Bigas 2011, Kumar, et al 2009). in leukaemogenesis. Data taken from: A wide range of allelic variants of TRIB1 have been http://Feb2014.archive.ensembl.org/Homo_sapiens/ reported. There are several genetic and protein Transcript/ProtVariations?db=core;g=ENSG000001 variations of TRIB1 listed on Ensembl. 73334;r=8:126442563- Table (3) shows the types of genetic variation of 126450647;t=ENST00000311922 TRIB1. Data taken from: Somatic http://Feb2014.archive.ensembl.org/Homo_sapiens/ Gene/Variation_Gene/Table?db=core;g=ENSG000 See online: Table 4: Protein variants of TRIB1. 00173334;r=8:126442563-126450647 Protein variants of TRIB1: Table 4 shows the protein Implicated in variants of TRIB1. Each variant is listed in order according to residue number. The table also lists Smooth muscle cells SIFT and Poly-Phen scores for the variations. SIFT TRIB1 is selectively over-expressed in chronically predicts whether an amino acid substitution is likely inflamed human atherosclerotic arteries and to affect protein function based on the sequence regulates vascular smooth muscle cell (VSMC) homology and the physico-chemical similarity chemotaxis and proliferation, a characteristic feature between the alternate amino acids. Each variant is of atherosclerosis via the JNK pathway (Sung, et al accompanied with a score and predictive 2007).

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Table 3: Genetic variations of TRIB1

Macrophages When mice are fed a high fat diet, mice lacking Trib1 in haematopoietic cells develop Trib1 is expressed in plaque resident macrophages in hypertriglyceridaemia and insulin resistance and a murine experimental atherosclerosis. The expression pro-inflammatory cytokine induction (Satoh, et al of Trib1 could be upregulated by IL-1, a major 2013). contributor to plaque development as the percentage of Trib1 expressing macrophages significantly Cancer decreases in ApoE -/- IL1R-/- double knockout mice TRIB1 has been associated with the development of compared to ApoE-/- controls. Overexpression of cancer and is considered as a leukaemia disease Trib1 in macrophages in vitro also leads to a gene. It was identified as a collaborator of Hoxa9 and significant attenuation (~70%) of IL-6 production Meis1 in myeloid leukaemogenesis (Jin, et al 2007). and suppressed IL-12 expression induced with a pro- Cooperative genes for Hoxa9/Meis1 were identified inflammatory stimulus (Sung, et al 2012). as common targets for retroviral integration, where It has also been shown that TRIB1 is involved in TRIB1 was identified as the most frequent common macrophage migration through interactions with site for integration in AML (Nakamura 2005). Table C/EBPβ and TNF-a. Knockdown of TRIB1 in 5 shows the common integration sites and candidate RAW246.7 cells resulted in an increase in TNF-a cooperative genes in TRIB1-induced AML production and C/EBPβ expression suggesting (Yokoyama and Nakamura 2011). TRIB1 alone is a TRIB1 may modulate TNF-a through C/EBPβ (Liu, transforming gene for myeloid cells and also et al 2013). significantly accelerates the development of Trib1 has been shown to also be involved with Hoxa9/Meis1 AML. adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue M2-like macrophages. Trib1 deficiency results in a significant reduction of M2-like macrophages. Mice lacking Trib1 in haematopoietic cells show a reduced adipocyte tissue mass and have evidence of increased lipolysis even on a normal diet. Supplementation of M2-like macrophages causes rescue suggesting the lack of these M2-like macrophages are responsible for lipolysis.

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Table 5: Common integration sites and candidate may be involved in a specific feature of lipid cooperative genes in TRIB1-induced AML. homeostasis (Kraja, et al 2011).
NOTE These genetic studies were further validated in in vivo models. Specific hepatic over-expression of Trib1 using an adenovirus vector reduced lipid plasma levels in a dose-dependent manner due to reduced VLDL production. Equally the opposite was seen in Trib1- knockout mice due to increased VLDL production. Interestingly when hepatic expression was reconstituted in knockout mice, VLDL-triglyceride production decreased to levels found in control mice (Burkhardt, et al 2010). The Oncogenesis precise mechanisms of Trib1 involvement in lipid Phosphorylation of ERK is enhanced in TRIB1 metabolism however are unknown.
transfected HeLa and Baf3 cells and leukaemia NOTE Burkhardt, et al (2010) further investigated by examining the mRNA levels of genes associated cells derived from TRIB1-induced AML upon cytokine stimulation (Jin, et al 2007). with lipid metabolism in the livers of Trib1 over- MEK1 and enhancement of MEK/ERK expressing and Trib1- deficient mice. A significant phosporylation is required for reactivity. Mutant decrease was found for genes involved in fatty acid lacking MEK1 binding site is unable to enhance oxidation such as Cpt1a (carnitine palmitoyltransferase 1A), Cpt2, and Acox1 (acyl- phosphorylation of ERK or extend self renewal in Coenzyme A oxidase 1) in Trib1 -/- mice. A bone marrow cells or induce AML/accelerate Hoxa9/Meis1 induced AML (Yokoyama, et al significant up-regulation of key lipogeneic genes 2010). was also found such as Acc1 (acetyl-Coenzyme A TRB1 has been implicated in human AML. TRIB1 is carboxylase), fatty acid synthesis (Fasn) and found on chromosome 8q24, 1.5Mb away from c- stearoyl-Coenzyme A desaturase 1(Scd1). Significant downregulation of these genes were MYC, the target of AML amplification. TRIB1 is found in Trib1-over expressing mice. These genes over-expressed even in some cases of AML when c- MYC amplification is not detected (Roethlisberger, have been noted to have effects on VLDL secretion et al 2007, Storlazzi, et al 2006) and plasma triglyceride and cholesterol levels. TRIB1 may also have a further role in lipogenesis. Cardiovascular Disease and TRIB1 over-expression resulted in a significant Atherosclerosis decrease in 35S-methionine labelled apoB secretion in HepG2 cells (human liver carcinoma cell line). Emerging evidence from several genome-wide The authors speculate that TRIB1-mediated association studies (GWAS) has implicated TRIB1 regulation of hepatic lipid availability might alter in the risk of cardiovascular disease and events the secretion of apoB particles via a mechanism specifically due to the levels of circulating lipids involving ER-associated degradation (ERAD) as (Kathiresan, et al 2008, Willer, et al 2008). previous data has shown a reduced availability or Two SNPs (rs2954029 and rs17321515) near the synthesis of lipid for apoB lipidation leads to co- TRIB1 gene have been implicated with triglyceride, translational targeting of apoB for ERAD LDL and HDL levels. A minor G allele at (Ginsberg, et al 2009). rs17321515 was associated with lower triglyceride and LDL cholesterol and higher HDL cholesterol Type 2 Diabetes levels. A TT -> TA -> AA genotypes at rs2954029 Trib1 has been hypothesised to have a regulatory were associated with step wise increases in the role in inflammation in adipoctyes that may levels of triglyceride, remnant cholesterol and apo- contribute towards obesity related type 2 diabetes. lipoprotein B, the primary apolipoproteins present Trib1 is specifically up-regulated during acute and on LDLs. Likewise HDL cholesterol levels chronic inflammation in white adipose tissue in decreased step-wise through the genotypes. mice. Trib1 knockout mice show it to be a key Additionally the genotypes were found to be regulator of inflammatory cytokines such as TNF-a significantly associated with increased risk of and are protected from high fat diet induced obesity ischemic heart disease (IHD) and increased risk of (Ostertag, et al 2010). It is proposed that Trib1 is MI. pro-inflammatory in the adipose by acting as a co- Further bivariate analysis showed TRIB1 activator for NF-kB inducing the expression of expression to be significantly associated with proinflammatory cytokines. triglyceride/ elevated blood pressure and triglyceride/HDL-cholesterol suggesting TRIB1 References

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DOCK1 (Dedicator of cytokinesis 1) Ping Li, Fung Zhao, Annie N. Cheung Departments of Pathology, the University of Hong Kong Shenzhen Hospital, Shenzhen (PL, ANC),, The University of Hong Kong, Hong Kong (FZ, AC), China

Published in Atlas Database: March 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/DOCK1ID40354ch10q26.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62524/03-2015-DOCK1ID40354ch10q26.pdf DOI: 10.4267/2042/62524 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA Dedicator of cytokinesis (DOCK) is a family of Description proteins with 11 members in mammal which can The DOCK1 gene is 6797 base pairs in length regulate cell motility, phagocytosis, myoblast fusion, encoding a large protein (about 180kDa). tumor suppression, neuronal polarization and adhesion. They are classified into four subfamilies A Transcription to D. Dock1 (Dock180), the founding member of the Variant (1) represents the longer transcript and family, is a large protein which includes an N- encodes the longer isoform (1). terminal SH3 domain and a flanking helical bundle Variant (2) uses an alternate splice site at an internal that are vital to the formation of a functioning exon, compared to variant 1. complex Dock1-ELMO1 (Gumienny et al.,2001; The encoded isoform (2) is shorter, compared to Grimsley et al.,2004; Komander et al., 2008). isoform 1. Genetic and biochemical studies show that DOCK1 acts as a guanine-nucleotide exchange factor (GEF) Protein for the small GTPase Rac1 (Diyokawa et al., 1998; Nolan et al., 1998). Rac1 is a small GTPase required Description for myoblast fusion in organisms such as fruit flies, Dock1 is a 180 kDa protein and largely responsible zebrafish and mice (Rochlin et al., 1998). In addition for regulating Rac-mediated polarization, migration, to playing an important role in a broad spectrum of phagocytosis of apoptotic cells, myoblasts fusion biological processes, numerous studies have and macrophages in vitro (Cte etal., 2005; Grimsley demonstrated contributions of DOCK members to etal., 2004; Pajcini et al., 2008) DOCK1 and its the development of cancer. Deciphering the detailed homologues in Drosophila (Myoblast city) and mechanisms by which DOCK proteins participate in C.elegans (CED-5) represent an evolutionarily tumorigenesis will shed light on the design of new conserved family of proteins which is called CDM treatment strategies. (CED-5, DOCK180, MBC)-family (Wu and Keywords Horvitz, 1998). DOCK1 DOCK1 has 6 splice variants with two protein- coding transcripts generating products consisting of Identity 1865 and 1886 amino acids respectively. The others are non-protein-coding transcripts. Other names: ced5, DOCK 180 An SH3 domain at the A- terminus and two domain HGNC (Hugo): DOCK1 CRK-binding sequences at the carboxyl end have Location: 10q26.13-q26.3 been identified in Dock1 (Hideki Hasegawa et al, 1996).

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"This research was originally published in Journal of Biological Chemistry. Premkumar L, et al. Structural basis of membrane targeting by the DOCK180 family of Rho family guanine exchange factors (Rho-GEFs). J Biol Chem. 2010, 23; 285(17):13211- 22. copyright the American Society for Biochemistry and Molecular Biology." (Premkumar L et al., 2010)

There are two high sequence homology named and 2 (DHR-1 and DHR-2, respectively) (Brugnera DHR-1 and DHR-2 among Dock family members et al., 2002; Cote and Vuori, 2002). DOCK1 contains (Jean Francois Cote and Kristiina Vuori, 2002). 1864 amino acids, a Src-homology 3 (SH3) domain DHR1 domain is 200-250 amino acids long that at the amino terminus, a few proline-rich motifs at binds phospholipids, whereas DHR2 domain of 450- the carboxyl terminus and a potential 550 amino acids is responsible for the guanine phosphatidylinositol trisphosphate (PtdInsP3)- nucleotide exchange activity (25022758). interacting motif near its C terminus (Hasegawa et Expression al.m 1996; Kobayashi et al 2001). Inactivation of the DHR-2 (also known as CZH2 or DOCKER) in DOCK1 is predominantly located in the cytoplasm DOCK1 can inhibit Rac activation, cell migration of cells. Nuclear localization of DOCK1 has also and clearance of apoptotic cells. This demonstrates been reported (Zhao et al., 2011). the necessity and sufficiency of DHR-2 to promote Function GDP/GTP exchange on various GTPases. DHR-2 This family is one of the GEFs being identified as has been suggested to consist of about 500 residues activators of Rho GTPases (Takai etal., 1996; (Brugnera et al., 2002; Cote and Vuori, 2002). DHR- Hasegawa et al., 1996; Erickson and Cerione, 2004). 2 domains of these family members have been DOCK1 activates Rho GTPase through facilitating shown to interact with the nucleotide-free form of the exchange of bound GDP for GTP. GTPases can Rho GTPase leading to the exchange of GDP for regulate actin cytoskeleton and be accountable for GTP(Meller et al., 2004; Lin et al., 2006; Miyamoto crucial biological functions, such as cell et al., 2006; Nishikimi et al 2005). DHR-1 domain phagocytosis, cell migration, cell proliferation, cell (also known as CZH1) is located upstream of DHR- survival, cell polarity, axonal guidance, transcription 2 domain (Meller et al., 2002) and is a novel PtdIns and intracellular trafficking (Iwasato et al., 2007; (3,4,5)P3-binding module which directly interacts Schmidt and Hall, 2002). In addition to playing an with phosphoinositides (PI),playing an important important role in a broad spectrum of biological role in Rac-mediated cell polarity and migration processes, numerous studies have demonstrated including myoblast fusion(Cote and Vuori, 2002). contribution of DOCK members to the development SH3 domains src-homology3 (SH3) domains are of cancer. protein-protein interaction modules in intracellular signal transduction. DOCK1 contains an SH3 Description domain at its N-terminus. SH3 domains have been DHR domain DOCK1 and its homologues in reported to bind to a proline-finch motif at the C- Drosophila (Myoblast city) and C.elegans (CED-5) terminus of ELMO (gumienny et al., 2001) which represent an evolutionarily conserved family of will be regulating the activation status of DOCK1. In proteins which is called CDM (CED-5, DOCK180, DOCK1, SH3 domain interacts with DHR-2 domain MBC)-family(Wu and Horvitz, 1998). This family is directly which is dependent on a proline-rich region one of the GEFs being identified as activators of Rho in DHR-2 domain, but inhibits some functions of the GTPases (Takai etal., 1996; Hasegawa et al., 1996; DHR-2 domain, such as binding to nucleotide-free Erickson and Cerione, 2004). The other family is Rac and facilitating GTP loading(Lu et al., 2005). Db1 family (Hart et al., 1991) and all their members Interaction with ELMO ELMO is an evolutionarily contain the Db1 Homology (DH) and the Pleckstrin conserved upstream regulator of Rac that takes effect Homology (PH) domains (Klinger et al., 2004; at the same step as DOCK 1 in phagocytosis of Srivastava et al., 1986; Worthylake te al., 2004; Feng apoptotic cells and cell migration (Gumienny et al., et al.,2002; Baird et al., 2005). While DH domains 2001). DOCK2-5 and DOCK 1 have an amino- directly catalyze GDP-GTP exchange, PH domains terminal Src homology (SH)-3 domain which can target proteins to membranes and mediate protein- interact with ELMO proteins and cooperate to protein interactions. DOCK 180-related proteins can activate Rac (Grimsley et al., 2004; Hiramoto et al., catalyze nucleotide exchange without homology to 2006). Other Dock-related proteins such as DOCK DH/PH domains, which are characterized by two 6-8 and DOCK9-11 cannot physically interact with protein domains named DOCK homology regions 1 ELMO proteins due to the lack of a recognizable

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SH3 domain. Some studies showed that deletion involved in signaling processes, such as cell mutants of DOCK 180 that fail to bind to ELMO adhesions, differentiation, migration, proliferation, could not efficiently activate Rac even when over- and phagocytosis of apoptotic cells (Clark and expressed in cells (Grimsley et al., 2004). Other Brugge, 1995; Juliano and Haskill, 1993; Richardson studies suggested that owing to auto-inhibition, the and Parsons, 1995). isolated DHR-2 appears to have much higher GEF Crk gene can be translated into two proteins, Crk-I activity than total DOCK 180 (Lu et al., 2005; Cote and Crk-II which are primarily isolated as oncogenic et al., 2007). Co-expression of ELMO is required to products (Mayer etal., 1988; Matsuda et al., 1992). relieve the auto-inhibited state (Lu et al., 2004; Santy DOCK180/DOCK1 can bind with the SH3 of the et al., 2005). The ELMO-DOCK1 complex is located Crk through PxxP region in its C-termini (Matsuda in the cytoplasm and will be translocated to the cell et al., 1996). It has been shown that DOCK 1 has two membrane, which is the key step for DOCK1 to C-terminal CRK-binding sequences. DOCK1 binds activate Rac (Debakker et al., 2004; Katoh and with Crk on the basis of a biochemical interaction. Negishi et al., 2003; Hasegawa et al., 1996; Katoh et The complex will be transiently translocated to the al., 2006). All three mammalian ELMO 1-3 proteins membrane resulting in changes in cell morphology have no obvious catalytic activity. They have three (Hasegawa et al., 1996). recognizable features including armadillo repeats at Essential for myoblast fusion Mammalian the N-terminus, an atypical PH domain and a myogenesis arises from the fusion of mononucleated complex prolin-rich region at the C-terminus. In fact, myoblasts. Myogenic cells fuse with each other to the functions of ELMO proteins in mediating Rac form multinucleated myotubes (Horsley and Pavlath, signaling remain largely unknown, and the 2004). Myoblast fusion is responsible for interaction between ELMO and DOCK is still development during embryogenesis and postnatal unclear. Some data indicate that there are two contact maintenance, growth, and helps regenerate injured regions between DOCK1 and ELMO1. The atypical tissue (Cerletti et al.m 2008; Rudnicki et al., 2008). ELMO1 PH domain and an uncharacterized region Proper regulation of myoblast fusion events between the SH3 and DHR-1 domains primarily determines myofiber length, appropriate contractile interact with each other. This interaction is sufficient capacity and muscle function(Allen et al., 1999). In to promote complex formation. N-terminal SH3 fact, the understanding of myoblast fusion of higher domain of DOCK1 and the C-terminal PxxP motifs vertebrates remains poor. Current knowledge is of ELMO1 are involved in the second contact largely derived from genetic analyses performed in (Komander et al., 2008). The PH domain and Drosophila(Chen and Olson, 2004; Taylor, 2003) proline-rich motifs are implicated in binding to and in vivo experiments in vertebrates (Cote and DOCK protein (Manishha et al., 2011). It has been Vuori, 2007). documented that the SH3 domain of DOCK1 binds In Drosophila melanogaster, fusion-competent to a proline-rich (pro-rich) motif at the C-terminus of myoblasts and founder cells regulate the formation ELMO, and this in turn would activate DOCK 1. of multinucleate muscle fibers. At cellular level, the This is the second interaction. So when either of processes of myoblast fusion include alignment, these motifs is mutated, the interaction of ELMO and actin cytoskeleton rearrangement at the contact sites DOCK1 is completely interrupted (Gumienny et al., and membrane fusion (Knudsen and Horwitz, 1977; 2011; Lu et al., 2005). The PH domain of ELMO Wakelam, 1985; Peckham, 2008; Duan and stabilizes the DOCK1-nucleotide-free Rac complex Gallagher, 2009). CDM superfamily consists of through binding "in trans" instead of interacting founding members such as MBC, human DOCK1, directly with either Rac or DOCK 180 (Lu et al, Caenorhabditis elegans CED-5 (Wu and Horvitz, 2004). The atypical PH domain of ELMO plays a 1998) and almost 20 additional members (Cote and crucial role in increasing the catalytic activity of Vuori, 2002). Myoblast city (mbc) is highly DOCK 180 towards Rac. ELMO1 or ELMO2, could important in Drosophila melanogaster embryo for coexpress with DOCK1, and overexpression of multinucleate fibers formation. ELMO1 together with DOCK1 synergistically It has been reported that Mbc together with ELMO, enhances phagocytosis(Zhou et al., 2001). ELMO function as an atypical bipartite GEF to directly PH domain could slightly enhance the catalytic control Rac1 in vivo. Drosophila eye experiments activity of DOCK 1 toward Rac by about twofold in show that Mbc and ELMO interaction will increase vitro. But this effect could be efficient in vivo the activity of Ras (Gersbrecht et al., 2008). because the Ced-12 PH domain mutations let Ced- Homology 12-null worms failed to rescue the migration defects (Lu et al., 2004). Therefore, the mechanism of action In mammals, dedicator of cytokinesis (DOCK) of Elmo remains inconclusive. Further studies are represents a new family of proteins comprising 11 required to clarify the controversies. members named DOCK1 (also known as Dock180) Binding to Crk Crk is an adaptor protein consisting to Dock11. They are classified into four subfamilies mostly of SH2 and SH3 domains which is also denoted Dock-A, -B, -C, -D. 11 members are

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classified as following: DOCK-A subfamily Burridge K, Wennerberg K. Rho and Rac take center stage. (DOCK1, DOCK2 and DOCK5); DOCK-B Cell. 2004 Jan 23;116(2):167-79 subfamily (DOCK3 and DOCK4); DOCK-C Côté JF, Vuori K. GEF what? Dock180 and related proteins subfamily (DOCK6, DOCK7 and DOCK8); DOCK- help Rac to polarize cells in new ways. Trends Cell Biol. D subfamily (DOCK9, DOCK10 and DOCK11) 2007 Aug;17(8):383-93 (Bridget Biersmith et al, 2011). Cerletti M, Shadrach JL, Jurga S, Sherwood R, Wagers AJ. Regulation and function of skeletal muscle stem cells. Cold Implicated in Spring Harb Symp Quant Biol. 2008;73:317-22 Chen EH, Olson EN. Towards a molecular pathway for Breast cancer myoblast fusion in Drosophila. Trends Cell Biol. 2004 Aug;14(8):452-60 Expression of DOCK1 correlates with poor survival for HER2+ and basal breast cancer patients Clark EA, Brugge JS. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr (Eckhardt et al., 2012; Perou et al., 2000). 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Dock1 and evolutionary convergence of Rho protein-guanine overexpression contributes to enhanced ovarian nucleotide exchange factor complexes. Biochemistry. 2004 cancer cell migration and invasion (Zhao F et al, Feb 3;43(4):837-42 2011). Feng H, Hu B, Vuori K, Sarkaria JN, Furnari FB, Cavenee WK, Cheng SY. EGFRvIII stimulates glioma growth and Lung cancer invasion through PKA-dependent serine phosphorylation of Dock1 can upregulate PTTG which could play a role Dock180. Oncogene. 2014 May 8;33(19):2504-12 in actin cytoskeleton remodeling, cell migration and Feng Q, Albeck JG, Cerione RA, Yang W. Regulation of the induction of epithelial mesenchymal transition in Cool/Pix proteins: key binding partners of the Cdc42/Rac lung cancer. The integrin alpha(V)beta(3)-FAK targets, the p21-activated kinases. J Biol Chem. 2002 Feb 15;277(7):5644-50 (focal adhesion kinase) signaling pathway is involved. (Shah PP et al, 2012). Feng Q, Baird D, Cerione RA. Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool- Gastric cancer 2/alpha-Pix. EMBO J. 2004 Sep 1;23(17):3492-504 Among genes involved in extracellular signal- Geisbrecht ER, Haralalka S, Swanson SK, Florens L, Washburn MP, Abmayr SM. Drosophila ELMO/CED-12 regulated kinase (ERK) downstream signaling interacts with Myoblast city to direct myoblast fusion and pathways activated by Cytotoxin-associated antigen ommatidial organization. Dev Biol. 2008 Feb 1;314(1):137- (CagA), a H. pylori immunoprotein, single 49 nucleotide polymorphism of Dock1 was found to be Grimsley CM, Kinchen JM, Tosello-Trampont AC, Brugnera significantly associated with risk of developing E, Haney LB, Lu M, Chen Q, Klingele D, Hengartner MO, gastric cancer with marginal gene dose effects. Ravichandran KS. Dock180 and ELMO1 proteins cooperate (Yang JJ et al, 2011). to promote evolutionarily conserved Rac-dependent cell migration. 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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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NR3C1 (nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor) Thomas D. Siamatras, Constantine A. Stratakis Section on Endocrinology, Genetics(SEGEN), Program on Developmental Endocrinology, Genetics, Eunice Kennedy Shriver National Institute of Child Health, Human Development(NICHD), NIH, Bethesda, Maryland 20892, USA [email protected]; [email protected]

Published in Atlas Database: February 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/NR3C1ID45665ch5q31.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62525/02-2015-NR3C1ID45665ch5q31.pdf DOI: 10.4267/2042/62525

network in the human body are influenced by this Abstract receptor and more specifically growth, reproduction, NR3C1 gene encodes the human glucocorticoid intermediary metabolism, immune and receptor(hGR), which is a ligand-dependent inflammatory reactions, as well as central nervous transcription factor and activates transcription of system and cardiovascular functions and glucocorticoid-responsive genes through binding lymphoproliferative disorders, cellular proliferation directly to glucocorticoid response elements(GREs) and differentiation in target tissues and normal renal in their promoter region, or modulating tubular function and thus water and electrolyte transcriptional activity of other transcription factors homeostasis are only some of the examples where through protein-protein interactions. hGR is hGR is implicated(Nicolaides, Galata, Kino, implicated in a broad spectrum of biochemical Chrousos, and Charmandari, 2010). physiologic functions, which are essential for life, and has also a key role in the maintenance of basal Identity and stress-related homeostasis. Almost 20% of the Other names: GCCR, GCR, GR, GRL genes expressed in human leukocytes are regulated positively or negatively by the hGR. Approximately HGNC (Hugo): NR3C1 every cellular, molecular and other physiologic Location: 5q31.3

Figure 1. Human hGR/NR3C1 gene 5' Flanking Region

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Fig. 2A. Genomic structure of the human glucocorticoid receptor (hGR/NR3C1) gene. It is composed of 9 exons. Alternative splicing of the primary transcript leads to the consequent two mRNA and proteins isoforms, hGRalpha and hGRbeta.

region spanning ~32,000-36,000 bps upstream of the DNA/RNA translation initiation site, while 1B, 1C, 1D, 1E, 1F, Description 1H and 1J position in the proximal promoter region located upstream up to ~5,000 bps. Alternate use of The human NR3C1 gene spans a length of 157,582 these promoters, differentiate the levels of GR bases. The NR3C1 structural gene is composed of protein isoforms in various tissues(Presul, Schmidt, nine exons and is located in chromosome 5 Kofler, and Helmberg, 2007). Different splicing and (5q31.3)(Hollenberg et al., 1985)(Figure 2A). translational GR isoforms originating from alternate Transcription promoters constitute up to 256 different The NR3C1 gene expresses mainly two mRNAs combinations of homo- and hetero-dimers with through alternative use of exons 9alpha and 9beta, different expression levels and transcriptional producing two highly homologous receptor activities. isoforms, termed alpha and beta(N. Z. Lu and This marked diversity in the transcription/translation Cidlowski, 2005). They are identical through amino of the GR gene allows cells/tissues to accommodate acid 727, with hGRalpha having an additional 50 appropriately to the circulating concentrations of amino acids and hGRbeta having an extra no glucocorticoids depending on their needs(Chrousos homologous 15 amino acids (Fig. 2A). Their and Kino, 2005a) and is responsible for the highly molecular weights of hGR9alpha and hGR9beta are stochastic nature of the glucocorticoid-signaling 97 and 94 kDa, respectively. Except these products, pathway (Chrousos and Kino, 2005b). the NR3C1 gene expresses GR? (gamma), which has Pseudogene one amino acid insertion due to splicing variation at exon 3-4 boundary,(Meijsing et al., 2009) and GR-P The NR3C1 gene has a pseudogene (NC3C1P1) in isoform, which has only 676 amino acids and is chromosome 16q (provided by RefSep 2012) encoded by an mRNA expressed from exons 1-7, but lacking exons 8 and 9 and unknown biologic Protein significance(Hagendorf et al., 2005). The human GR gene has eleven different promoters with their Description alternative first exons (1A1, 1A2, 1A3, 1B, 1C, 1D, The human NR3C1 protein sequence 1E, 1F, 1H, 1I and 1J) (Figure 1). Therefore, the (NP_000167.1)consists of 777 amino acids and has human GR gene can produce eleven different a MW of 85659 Da. Without the presence of the transcripts alternating the different promoters that ligand, hGRalpha takes part in a heteromultimeric encode the same GR proteins having a common exon cytoplasmic complex with chaperone Heat Shock 2, which contains the translating ATG codon. 1A1, Proteins (HSP)90,70,50 immunophilins and other 1A2, 1A3 and 1I are located in the distal promoter proteins.

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Fig 2B. Functional domains of the NR3C1/hGRalpha. AF, activation function; DBD, DNA-binding domain; HSPs, heat shock proteins; LBD, ligand-binding domains; NLS, nuclear localization signal.

As soon as it binds to the ligand, dissociates from the of transactivation domain, termed activation previous complex and FK506-binding function (AF)-1, located between amino acids 77 and immunophilin heat shock protein 56 takes its place, 262, activated when is ligand-independent. It has an thereby connecting to dynein and mediating the important role in the interaction of the receptor with transportation to the nucleus, where it dissociates molecules necessary for stimulation of transcription, (Czar, Lyons, Welsh, Renoir, and Pratt, 1995). When such as coactivators, chromatin modulators and it reaches the nucleus, the receptor binds as a basal transcription factors. The DNA-binding homodimer to various Glucocorticoid Response domain (DBD) consists of amino acids 420-480, Elements(GREs) sequences in the promoter region contains two zinc finger motifs through which binds of many genes, and as a heterodimer with NR3C2 or to specific DNA sequences, such as the the retinoid X receptor, thus regulating their glucocorticoid response elements (GREs) in the expression either positively or negatively depending promoter region(s) of specific genes. The DBD also on GRE sequence and promoter context. The ligand- contains sequences important for receptor activated hGRalpha modulates gene expression dimerization and nuclear translocation. The hinge without binding to GREs, by interracting also with region gives flexibility connecting DBD with LBD other transcription factors, such as activator protein- by conferring structural flexibility in the receptor 1(AP-1), nuclear factor-kB (NF-kB), p53 and signal dimers, allowing single receptor dimmer to interact transducers and activators of transcription (STATs). with multiple GREs and different sequences. The For the transcription when hGRalpha uses its ligand-binding domain (LBD) consist of amino acids transcriptional activation domains, AF-1 and AF-2, 481-777, binds ligand glucocorticoid with its ligand- as surfaces to interact with specific nuclear receptor binding pocket and contains a second transactivation coactivators and chromatin-remodeling complexes, domain, the ligand-depended AF-2 which plays an then these coactivators form a bridge between DNA- important role in the glucocorticoid-induced bound hGRalpha and the transcription initiation stimulation of hGR transcriptional activity, by complex, conveying the transmission of the interacting with coactivators containing LxxLL glucocorticoid signal to the RNA polymerase II and motifs. LBD takes part in the complex formation its ancillary components leading to initiation and with heat shock proteins, in the process of nuclear promotion of the transcription. As a member of the translocation and receptor dimerization (Nicolaides, nuclear receptor superfamily, hGR has 3 major et al., 2010). domains: the N-terminal domain (NTD), middle DNA-binding domain (DBD) and the C-terminal Expression ligand-binding domain (LBD) as illustrated in (Fig. Ubiquitous. Almost all human tissues and cells are 2B). Using the typical nomenclature for NR expressing the hGRalpha. The GR expression has subdomains, hGR consists of the amino-terminal been reported in the Bone Marrow, Monocytes, A/B region (corresponding to NTD), C (DBD), D Dendritic Cells, NK Cells, T Cells (CD4+), T Cells (hinge region) and E (LBD) regions, without having (CD8+), B Lymphoblasts, B Cells, Lymph Node, the F region. The N-terminal domain (NTD) consist Spleen, Thymus, Retina, Heart, Cardiac Myocytes,

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Atrioventricular Node, Smooth Muscle, Skeletal affinity of the mutant receptors for the ligand, altered Muscle, Appendix, Pancreatic Islet, Small Intestine, subcellular localization, delayed nuclear Colon, Adipocyte, Kidney, Liver, Lung, Trachea, translocation after binding to the ligand, reduced Bronchial Epithelium, Tongue, Thyroid, Salivary ability to bind with GREs and decreased Gland, Adrenal Gland, Breast, Skin, Ovary, Uterus transcriptional activity, altering the exertion of a Corpus, Uterin Cervix, Placenta, Fetal Brain, Liver, dominant negative effect upon the wild-type Lung and thyroid, Tonsil, Prefrontal Cortex, receptor, reduced interaction with other coactivators Cingulate Cortex, Parietal Lobe, Temporal Lobe, and reduced motility within the nucleus are some of Occipital Lobe, Ciliary Ganglion, Globus Pallidus, the mechanisms of mutant hGR (Charmandari, Olfactory Bulb, Thalamus, Hypothalamus, Chrousos, and Kino, 2009). Although, most Subthalamic Nucleus, Caudate Nucleus, Amygdala, mutations of the NR3C1 gene exert generalized Pons, Medulla Oblongata, SupCervical Ganglion, glucocorticoid resistance there is one mutation Dorsal Root Ganglion, Trigeminal Ganglion, Spinal reported to date in the hGRalpha NTD region that Cord, Pineal (Day)and Pineal (Night), Pituitary, replaces aspartic acid at amino acid 401 by histidine Prostate, Testis Germ, Testis Intersitial, Testis (D401H) facilitating the mediated gene expression Leydig cells. (Charmandari et al., 2008). Interindividual variations Localisation in tissue sensitivity to glucocorticoids have been described within the normal population and are In the absence of ligand, hGRalpha resides mostly in mainly attributed to polymorphisms in the hGR the cell cytoplasm, but upon ligand-induced gene. A heterozygous polymorphism replacing activation, the receptor dissociates from the aspartic acid to serine at amino acid 363 mildly multiprotein complex and translocate into the increases transcriptional activity, and arginine to nucleus. After binding to specific DNA responsive lysine replacement at amino acid 23 is associated elements remains within the nucleus for a with relative glucocorticoid resistance. A single considerable length of time and is then exported to nucleotide polymorphism that replaces A with G at the cytoplasm. It is also present in the Mitochondrion the nucleotide 3669 (A3669G) located in the 3' end and Plasma membrane. The isoform Beta is mainly of exon 9beta increases the stability of GRbeta expressed in the nucleus. mRNA, leading to greater inhibition of GRalpha- Function induced transcriptional activity and thus glucocorticoid resistance (Syed et al., 2006). hGR has a dual mode of transcriptional activity: It is worth mentioning also the fact that there is a acting either as a glucocorticoid-dependent plethora of laboratory generated mutated GR transcription factor, binding mainly to proteins, which provides an interesting tool for glucocorticoid response elements (GRE) or exploring hGR structure-function relationships. functioning as a modulator of other transcription (Beck, De Bosscher, and Haegeman, 2011) factors through protein-protein interaction. Post- translational modifications (PTMs), such as phosphorylation, acetylation, ubiqutilation and Implicated in nitrosylation, play also an important role in the Normal physiology and homeostasis regulation of GR activity, affecting the receptor stability, subcellular localization, and also The stochastic nature of glucocorticoid signaling interaction between GR and other proteins, pathways(Chrousos and Kino, 2005b), and the influencing finally the transcriptional activity. variable effect that hGR gene Recent studies have demonstrated that the circadian mutations/polymorphisms exert on glucocorticoid rhythm transcription factors CLOCK and BMAL1 signal transduction, suggest that alterations in hGR repress GR-induced transcriptional activity by action affect many critical biological processes acetylating several lysine residues (Kino and including the behavioural and physiologic responses Chrousos, 2011). to stress, the immune and inflammatory reaction, the process of sleep, growth and reproduction. It is an Homology extremely important component of many cellular Is a member of the nuclear hormone receptor family, and molecular signaling pathways in maintaining NR3 subfamily. homeostasis and preserving normal physiology (Charmandari and Kino, 2010) Mutations Primary MyeloFibrosis(PMF) Mutations or polymorphisms in the hGR gene impair The frequency of A3669G single nucleotide one or more of the molecular mechanisms of polymorphism (SNP) of human glucocorticoid hGRalpha action and as a final consequence alter the receptor is increased in patients with polycythemia tissue sensitivity to glucocorticoids. Reduced vera compared to normal population.

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Table 1: Reported mutations in the hGR/NR3C1 gene causing either generalized glucocorticoid resistance or increased sensitivity.

This variant allele at the homozygous state (G/G) is However, GC-resistance is major therapeutic considered also a susceptibility allele to PMF. problem without yet a clear molecular mechanism. Especially, in cooperation with other mutated genes In two key models of acute lymphoblastic leukemia such as JAK2V617F, the glucocorticoid receptor the GCs resistance was associated with mutations at A3669G SNP contributes to the phenotype of excess the level of the glucocorticoid receptor (some of myeloproliferation, and determination of Blast which were newly identified; previously not Transformation (Poletto et al., 2012). associated with GC resistance, such as: A484D, Acute Lymphoblastic Leukemia (ALL) P515H, L756N, Y663H, L680P, and R714W0 (Schmidt et al., 2006). The survival probabilities in Glucocorticoids (GC) are pivotal in the treatment of children with ALL were associated with acute lymphoblastic leukemia (ALL) and other homozygocity of G allele of the NR3C1 BcII lymphoid malignancies, since they induce apoptosis polymorphism, presenting a worse progression and in lymphoblasts. Although research studies prognosis of the disease (Fleury et al., 2004), and delineated the transcriptional response to GCs in two also three other NR3C1 SNPs polymorphism; ALL cell lines (precursor B-ALL and T-childhood ?627A/G, intron2 +646)C/T and 9bT/C were ALL), forming mainly the basis for the molecular associated with dismal childhood cALL outcome understanding of their antileukemic (and perhaps with reduced event-free and overall survival (Labuda other) effects; questions on their induction of et al., 2010) apoptosis and cell cycle arrest in leukemic cell lines studied still exists. Although a wide range of Multiple Myeloma possible interacting genes were analysed (c-myc and Downregulation of GR mRNA in a glucocorticoid Cyclin D3, BMF, MCL1, Bcl-XL, PMAIP1/Noxa, resistant Multiple Myeloma cell line is in partly ZBTB16, SLA, PFKFB2, TNFAIP8, explained by the transcriptional block at intron B of GPR65/TDAG8,DDIT4/Dig2, MAP2K3, MYC, NR3C1 (Sanchez-Vega and Gandhi, 2009). Novel mir17~92, TXNIP) indications were that they had Glucocorticoid-based therapy based on combination only moderate influence if any, on GC-induced of selective glucocorticoid receptor (GR) activators apoptosis in the experimental systems mentioned (SEGRA) and proteasome inhibitors are effective in with the only exception of members of the BCL2 the treatment of Multiple Myeoloma, circumventing gene family. Could it be a single critical gene the undesired effects of chronic use of downstream responsible for the GR apoptosis glucocorticosteroids. The novel non-steroidal GR induction or rather a GC-regulated network of genes; modulator Compound A (CpdA) retains this is still under investigation (Rainer et al., 2012). glucocorticoid-like anti-inflammatory and anti-

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cancer activity and has fewer side effects compared analysis revealed that there was significantly to glucocorticoids. (Sommer and Ray, 2008) CpdA increased DNA methylation in the 1C promoter of strongly inhibits growth and viability of multiple the NR3C1, which was negatively correlated with myeloma cells in GR-dependent manner. There is GR protein expression in tested human SCLC cells evidence for an important GR-dependent (Kay et al., 2011). cooperation between CpdA and proteasome- inhibitor Bortezomib in eliminating survival of Pituitary Adenoma and multiple myeloma cells (Lesovaya et al., 2013). Adrenocortical tumours Osteosarcoma (OS) The expression of the GR is an essential element of the negative closed feedback loop formed by Osteoblasts are highly sensitive to glucocorticoids, corticotropin-releasing hormone, which reduce their proliferation and show apoptosis adrenocorticotropic hormone, and cortisol in the upon glucocorticoid treatment. In contrast to normal context of the hypothalamic-pituitary-adrenal (HPA) osteoblasts, OS cells express 11beta-hydroxysteroid axis. The variability in expression and function of dehydrogenase type 2 (11beta-HSD2), which the GR in pituitary and adrenocortical cells is converts cortisol (active) to cortisone (inactive), and responsible for the considerable differences in thus, expression of 11beta-HSD2 renders OS cells function of this loop. Some of the variation can be resistant to glucocorticoids and subsequent ascribed to functional GR polymorphism, which apoptosis. High 11beta-HSD2 expression is may also predispose to adrenocortical tumour correlated with a poor response to GCs treatment in formation (Majnik et al., 2006). This variability may Osteosarcoma (Patel et al., 2012). explain why it is so difficult to interpret (or Prostate Cancer reproduce) results regarding the analysis of Glucocorticoids are used in clinical practise for diagnostic testing of the HPA axis in patients with patients with hormone-refractory prostate cancer. pituitary adenomas (Cushing disease) or They inhibit tumour angiogenesis and subsequent adrenocortical tumours (Cushing syndrome). tumour growth, possibly by down-regulating (Briassoulis, Damjanovic, Xekouki, Lefebvre, and vascular endothelial growth factor (VEGF) and Stratakis, 2011) interleukin-8 and additionally supressing tumour- Astrocytoma associated lymphangiogenesis by down-regulating VEGF-C through glucocorticoid receptor (Yano et Glial tumour cells are sensitive to glucocorticoids al., 2006). (GC), which cross the blood-brain barrier and are used for certain glial tumours treatment. Although Ectopic ACTH-producing tumours low-grade malignant human astrocytoma cells did Non-pituitary (ectopic) ACTH secretion generally is not present a significant hGRalpha expression they not responding to exogenous glucocorticoid did endogenously express the Cortisol Binding administration. DMS-79 small-cell lung carcinoma Globulin (CBG). Upon GCs treatment CBG is cells derived from these ectopic ACTH-producing immediately released (possibly in a nongenomic tumours express an abnormal GR mRNA which way) suggesting the apoptosis of certain glial encodes a protein lacking the steroids-binding tumours is partly associated with this phenomenon domain leading to misfunctional characteristics of of CBG-release and not through hGR (Pusch, this ligand-activated transcription factor. The Wegmann, Caldwell, and Jirikowski, 2009) abnormal transcripts in these cells arrived from normal GR genes by aberrant splicing of intron G Sarkoma Kaposi (KS) (between exons 7 and 8). Although GR signalling Human Immunodeficiency Virus/Acquired defects seem likely to cause glucocorticoid Immunodeficiency Syndrome (HIV/AIDS)-KS cells resistance of non-pituitary tumours, the suppression expressed unusually high levels of glucocorticoid at high doses of exogenous glucocorticoids as is receptor protein and at the same time were appeared particularly in bronchial carcinoids significantly stimulated by glucocorticoids implicates other potential mechanisms are also (Enwonwu, 1996). The increased expression of possible(Parks, Turney, Detera-Wadleigh, and functional GRs was associated with four cytokines, Kovacs, 1998). namely interleukin-1beta, interleukin-6, tumour Non-Small Cell Lung Cancer (NSCLC) and Small necrosis factor-alpha, and oncostatin M, all of which Cell Lung Cancer (SCLC). High levels of hGR in are known autocrine growth factors for AIDS-KS patients with advanced NSCLC are associated with cells. The high levels of GR expression in these cells better outcome (Y. S. Lu et al., 2006). GR expression and the up-regulation of GRs by KS-growth- causes activation of the apoptotic pathway as promoting factors are associated with the enhanced evidenced by marked induction of caspase-3 and sustained sensitivity to the actions of activity. On the other hand methylation glucocorticoids (Guo et al., 1996).

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Cancers of the Digestive System expression of GR in terms of progression of Breast Cancer. It is strongly expressed in metaplastic GR is strongly expressed in oesophageal squamous carcinomas and malignant phyllodes tumour but epithelia, pancreatic islet cells and hepatocytes, but there is lack of important GR expression in great generally it has a weak or negative expression in majority of non-metaplastic carcinomas (Lien et al., non-squamous epithelia (gastric and colorectal 2006). Glucocorticoid Receptor and Nuclear Factor adenocarcinomas). Chemotherapy resistance in Nf?BETA signaling pathways appears to be an tumours originating from the above mentioned important phenomenon in the initiation, progression tumour-cells induced by the use of Dexamethasone and recurrence of inflammatory Breast Cancer (BC), (DEX) is suggesting that GR expression may be wherein NFkB and glucocorticoid receptor (GR) are biologically important in some GR-expressing critical transcription factors in regulating carcinomas (Lien et al., 2008). In Gastric inflammation. NFkB is generally pro-inflammatory, Carcinoma, NR3C1 methylation was a useful marker while GR is anti-inflammatory. It is the crosstalk for identifying distinct type-subsets of these between these two transcription factors that exert a carcinomas (Kang et al., 2008). Analysis of tissues crucial function in determining the survival or sections in well differentiated pancreatic apoptosis of BC cells. However, the use of adenocarcinomas revealed a strong positivity Glucocorticosteroids (GCs) and their biological (mainly cytoplasmic) for Glucocorticoid receptor, effects through GR unexpectedly promote cancer but interestingly the liver metastasis of these cell survival and induce chemo-resistance in BC tumours was completely negative(Bekasi and (Ling and Kumar, 2012). Curcumin which exerts a Zalatnai, 2009). wide spectrum of anti-inflammatory, anti-oxidant Colorectal cancer and anti-cancer activities is under investigation as chemopreventive and chemotherapeutic agent which A significant difference in mRNA expression main action is through GR and NFkB modificatory (reduced) of hGRalpha, 11beta-HSD- expressions (Sinha, Biswas, Sung, Aggarwal, and 1(overexpressed) and other glucocorticoid Bishayee, 2012). metabolism-related genes was observed in colorectal adenocarcinomas which were associated with the Coronary Artery Disease downregulation of E-cadherin mRNA, a critical Development of Epicardial Adipose Tissue is not required step in the progress of tumor invasiveness, augmented by glucocorticoids, as does the connecting these genes to carcinogenesis and Subcutaneous Adipose Tissue. The decreased total progression of colorectal cancer(Storkson et al., GR mRNA expression and reduced associated 2012). Cancer-specific hypermethylation of the transcripts in promoter B and C into this specific NR3C1 gene was identified in colorectal tumors tissue; suggest a protective role for Coronary (Lind et al., 2006) and FK506-binding proteins physiology (Silaghi, Silaghi, Scridon, Pais, and (FKBPS) suppressed the proliferation of colorectal Achard, 2012) adenocarcinoma possibly due to the suppression of function of the glucocorticoid receptor (Mukaide et Bronchial asthma al., 2008). The N363S single nucleotide polymorphisms (SNPs) of the hGR/NR3C1 gene are supposed to Cervical Cancer play an important role in the development of GR expression is observed in cervical low and high- bronchial asthma and in the alteration of sensitivity grade intraepithelial neoplasia and in invasive to Glucocorticosteroids in severe bronchial asthma cervical squamous cell carcinoma. Since (Panek et al., 2012). At the cellular level the glucocorticoids act also as cofactor with human impairment of GR-Ser211 phosphorylation in papillomaviruses in the etiology of cervical cancer, Airway Smooth Muscle cells by proasthmatic and inhibit chemotherapy or radiation-induced cytokines drastically reduced their responsiveness to apoptosis, the persistence of GR in cervix cancer glucocorticoids (Bouazza et al., 2012) and the use of cells questions the combined use of glucocorticoid Dexamethasone repressed the glucocorticosteroids with antineoplastic drugs or production of mucin glycoproteins in lung epithelial other agents in clinical practise settings for women cancer cells. This repression is induced by lower presenting with cervix cancer. (Buxant, Bucella, expression of mucin genes, which is mediated by the Anaf, Simon, and Noel, 2009) glucocorticoid receptor (GR) and two glucocorticoid Breast cancer response elements (GREs) in the mucin gene promoter region (Chen et al., 2012). Glucocorticoid receptor (GR) is playing an important role in mammary gland development and Adult Onset Chronic Diseases differentiation, and has been implicated in breast Extreme maternal psychosocial stressors and early tumourigenesis without actually knowing the exact life experiences in utero and in newborns modify biochemical pathways or consequence of this unique locus-specific epigenetic marks in the newborn

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correlating these events with the newborn Czar MJ, Lyons RH, Welsh MJ, Renoir JM, Pratt WB. methylation in the promoter of the glucocorticoid Evidence that the FK506-binding immunophilin heat shock protein 56 is required for trafficking of the glucocorticoid receptor NR3C1. receptor from the cytoplasm to the nucleus. Mol Endocrinol. Increased methylation impairs plasticity in 1995 Nov;9(11):1549-60 subsequent NR3C1 gene expression and accordingly Enwonwu CO. Pathogenesis of oral Kaposi's Sarcoma in the range of future stress adaptation responses, HIV-infection: relevance of endogenous glucocorticoid resulting possibly in increased risk for adult-onset excess in blood and saliva. Eur J Cancer B Oral Oncol. 1996 diseases (Mulligan, D'Errico, Stees, and Hughes, Jul;32B(4):271-4 2012). Fleury I, Primeau M, Doreau A, Costea I, Moghrabi A, Sinnett D, Krajinovic M. 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Research resource: transcriptional and in vitro effect of glucocorticoid on cell growth and response to glucocorticoids in childhood acute chemosensitivity. Lung Cancer. 2006 Sep;53(3):303-10 lymphoblastic leukemia. Mol Endocrinol. 2012 Jan;26(1):178-93 Majnik J, Patocs A, Balogh K, Toth M, Gergics P, Szappanos A, Mondok A, Borgulya G, Panczel P, Sánchez-Vega B, Gandhi V. Glucocorticoid resistance in a Prohaszka Z, Racz K. Overrepresentation of the N363S multiple myeloma cell line is regulated by a transcription variant of the glucocorticoid receptor gene in patients with elongation block in the glucocorticoid receptor gene bilateral adrenal incidentalomas. J Clin Endocrinol Metab. (NR3C1). Br J Haematol. 2009 Mar;144(6):856-64 2006 Jul;91(7):2796-9 Schmidt S, Irving JA, Minto L, Matheson E, Nicholson L, Meijsing SH, Pufall MA, So AY, Bates DL, Chen L, Ploner A, Parson W, Kofler A, Amort M, Erdel M, Hall A, Yamamoto KR. DNA binding site sequence directs Kofler R. 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Curr Drug Targets. 2012 changes at NR3C1 in newborns associate with maternal Dec;13(14):1799-819 prenatal stress exposure and newborn birth weight. Epigenetics. 2012 Aug;7(8):853-7 Sommer P, Ray DW. Novel therapeutic agents targeting the glucocorticoid receptor for inflammation and cancer. Curr Nicolaides NC, Galata Z, Kino T, Chrousos GP, Opin Investig Drugs. 2008 Oct;9(10):1070-7 Charmandari E. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 2010 Størkson RH, Aamodt R, Vetvik KK, Pietilainen K, Bukholm Jan;75(1):1-12 G, Jonsdottir K, Vollan HS, Sonerud T, Lüders T, Jacobsen MB, Bukholm IR. mRNA expression of adipocytokines and Panek M, Pietras T, Antczak A, Fabijan A, Przemęcka M, glucocorticoid-related genes are associated with Górski P, Kuna P, Szemraj J. The N363S and I559N single downregulation of E-cadherin mRNA in colorectal nucleotide polymorphisms of the h-GR/NR3C1 gene in adenocarcinomas. Int J Colorectal Dis. 2012 patients with bronchial asthma. Int J Mol Med. 2012 Aug;27(8):1021-7 Jul;30(1):142-50 Syed AA, Irving JA, Redfern CP, Hall AG, Unwin NC, White Parks LL, Turney MK, Detera-Wadleigh S, Kovacs WJ. An M, Bhopal RS, Weaver JU. Association of glucocorticoid ACTH-producing small cell lung cancer expresses aberrant receptor polymorphism A3669G in exon 9beta with reduced glucocorticoid receptor transcripts from a normal gene. Mol central adiposity in women. Obesity (Silver Spring). 2006 Cell Endocrinol. 1998 Jul 25;142(1-2):175-81 May;14(5):759-64 Patel P, Hardy R, Sumathi V, Bartle G, Kindblom LG, Grimer Yano A, Fujii Y, Iwai A, Kawakami S, Kageyama Y, Kihara R, Bujalska I, Stewart PM, Rabbitt E, Gittoes NJ, Cooper K. Glucocorticoids suppress tumor lymphangiogenesis of MS. Expression of 11β-hydroxysteroid dehydrogenase prostate cancer cells. Clin Cancer Res. 2006 Oct 15;12(20 enzymes in human osteosarcoma: potential role in Pt 1):6012-7 pathogenesis and as targets for treatments. Endocr Relat Cancer. 2012 Aug;19(4):589-98 This article should be referenced as such: Poletto V, Rosti V, Villani L, Catarsi P, Carolei A, Campanelli Siamatras TD, Stratakis CA. NR3C1 (nuclear receptor R, Massa M, Martinetti M, Viarengo G, Malovini A, subfamily 3, group C, member 1/glucocorticoid receptor). Migliaccio AR, Barosi G. A3669G Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3):121-129. polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation. Blood. 2012 Oct 11;120(15):3112-7

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3) 129 Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Gene Section Review

CCND1 (B-cell leukemia/lymphoma 1) Shreya Sarkar, Chinmay Kumar Panda Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India; [email protected]

Published in Atlas Database: April 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/BCL1ID36.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62526/04-2015-BCL1ID36.pdf DOI: 10.4267/2042/62526 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

about 13.38 Kb (precisely 13,388 bases), contains 5 Abstract exons and is arranged in a telomere to centromere orientation. Review on CCND1, with data on DNA, on the protein encoded, and where the gene is implicated. Transcription Keywords According to Ensembl, the full length, functional CCND1; Cell cycle transcript of CCND1 (Transcript ID ENST00000227507) is 4307 bp in length, encoding Identity 5 coding exons. From the total of 6 transcripts generated, only two HGNC (Hugo): CCND1 are protein coding. Location: 11q13.3 Pseudogene Other names: BCL1, U21B31, D11S287E None reported. Protein Description The full length CCND1 protein has a length of 295 amino acids, having a molecular weight of 33729 Da. CCND1 is a member of the cyclin family, Cyclin D subfamily and contains 1 cyclin N-terminal domain.

BCL1 (11q13) - Courtesy Mariano Rocchi. Localisation Nuclear, cytoplasmic and membrane. Accumulation DNA/RNA of CCND1- CDK4 complexes occur in the nuclear membrane, which are then transported to the nucleus Description through interactions with KIP-CIP family member Located in the long (q) arm of chromosome 11 in the proteins (By similarity, a LaBaer et. al.,1997). 13th band, the length of the CCND 1 gene is

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The figure shows the chromosomal location of CCND1 (Red line). Image courtesy genecards.org

Diagram shows the different transcripts of CCND1 (BROWN, BLUE AND MAROON BOXES). Beginning of boxes represents transcription start sites. Filled areas represent translated regions. The brown box representing transcript CCND- 001 forms the full length, active protein. Image adapted from Ensembl.org

Schematic diagram of full length CCND1, showing different domains. Adapted from PDB P24385. Data origin/ Colour codes: Data in Green originates from UniProtKB.; Data in blue originates from PDB. Secstruc- Secondary structure projected from representative PDB entries onto the UniProt sequence. a. Red box- Helix. b. Grey tube- Coil. Data in red indicates combined ranges of Homology Models from SBKB and the Protein Model Portal.

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The RNA expression data of CCND1 based on data from BioGPS, Illumina Human BodyMap, and SAGE, with SAGE tags from CGAP, Figure shows RNA expression data (presence/absence) for RNA genes is according to H-InvDB, NONCODE, miRBase, and RNAdb. The expression images based on data from BioGPS, Illumina Human BodyMap, and SAGE, with SAGE tags from CGAP. BioGPS: 76 normal tissues were used and compartments hybridized against HG-U133A, with Affeymetrix MAS5 algorithm used in array processing. Illumina body map: Transcripts were mapped to genes from 16 normal human tissues by sequencing. Cufflinks program was used to calculate Fragments per Kilobase of exon per Million fragments mapped (FPKM) and rescaled by multiplying FPKM by 100 and calculating the root. CGAP: SAGE Normal. For Serial Analysis of Gene Expression (SAGE) of 19 normal human tissues, Hs frequencies and Hs libraries in CGAP datasets are mined for information regarding the number of SAGE tags per tissue. Unigene clustering was applied to Tags, followed by a particular gene by mining Hs best gene, Hs best tag and Hs GeneData. The number of appearances of the corresponding tag divided by the total number of tags in libraries derived from that tissue was used in calculating the level of expression of a particular gene, which were then rescaled by making the genomic mean of all tissues equal. Intermediate between log and linear scales are normalized intensities drawn on root scale, with values not comparable between datasets (i.e. Microarray, RNAseq and SAGE). Figure courtesy: genecards.org.

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Presentation of protein expression images for 35 tissues, fluids and cells. Data sources: MOPED - Eugene Kolker, Bioinformatics & High-throughput Analysis Lab, Seattle Children's Research Institute; PaxDb - Christian von Mering, Bioinformatics Group, Institute of Molecular Life Sciences, University of Zurich; MAXQB - Matthias Mann, Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Germany. The data was normalized as follows: For each sample, ppm protein values were calculated, if not provided so by data sources. For each sample from MAXQB, iBAQ expression values were divided by sum of values of each sample, and multiplied by 1,000,000. For all samples, data was gene centrically aggregated by summing expression values of all isoforms for each gene. For better visualization of graphs, expression values are drawn on a root scale, which is an intermediate between log and linear scales as used for our mRNA expression graphs (PMID 12519968).

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Expression in tissues: Top: Cyclin D1 overexpression in keratoacanthomas (KAs) and squamous cell carcinomas (SCCs). CCND1 (brown), counterstain hemalaun (blue). (a) Normal skin and (b) actinic keratosis, a precursor lesion of SCCs. (c-f) Representative KAs (c) Higher magnification of a different tumor (d); medium expression (e); and low expression (f) of cyclin D1. Bar=50 micro-m. Image courtesy Burnworth et. al., 2006. Middle: The figure shows the localization of CCND1 in Ramos cells. Image courtesy Abcam. Bottom: Expression during cell cycle: Image shows the levels expression of CCND1 during different phases of the cell cycle (left panel) and the function associated in each phase (right). Image courtesy kinexux.ca (left) and Yang et. al., 2006 (right).

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Function E/CDK2-containing complexes (Polyak et al., 1994; Sherr and Roberts, 1999). CCND1 binds and activates the G1 cyclin dependent CCND1 phosphorylates Smad3 and inhibits its kinases, Cdk4 and Cdk6. The complex then transcriptional activity and antiproliferative function phosphorylates and inhibits members of the (Matsuura et. al., 2004). retinoblastoma (RB) family of protein including RB1, thereby regulating the G1/S transition in the Homology cell cycle (Kato et al., 1993). The CCND1 gene is conserved in chimpanzee, CCND1 has a kinase-independent function of Rhesus monkey, dog, cow, mouse, rat, chicken, sequestering CDK inhibitors such as p27 Kip1 and zebrafish, and frog (According to Homologene, p21Cip1and promoting efficient activation of Cyclin NCBI).

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Top: String model depicting probable binding partners on CCND1. Image adapted from string-db.org; Bottom: The figure shows the different proteins with which CCND1 interact and the different functions that result from such interactions. Picture courtesy: Pestell, 2013.

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Gene tree of CCND1 Human has been encircled in red. Adapted from ensembl.org.

Figure shows the predicted miRNA binding sites in the 3' UTR of CCND1. Image courtesy TargetScan 6.2.

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Figure represents the types and percentages of various of mutations observed in CCND1. Image adapted from COSMIC gene analysis.

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Figure represents the types and percentages of various of mutations observed in CCND1. Image adapted from COSMIC gene analysis.

Mutations and copy number variations of CCND1 in different organs. Red bar: Loss. Grey bar: Gain. Adapted from COSMIC gene analysis.

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miR-302 in Endometrial cell line Ishikawa Mutations Directly targets CCND1 and significantly inhibited Somatic protein expression (Yan et. al., 2014). CD95 somatic mutations have been reported in miR-449-a in Gastric cancer cell line SGC7901 several cancers. miR-449a inhibited SGC7901 cells proliferation and enhanced cisplatin chemosensitivity by Epigenetics downregulating expression of CCND1, respectively, CCND1 and miRNAs: via directly targeting the 3'-untranslated regions of miR365 CCND1 mRNA (Hu et. al., 2014). in Gastric cancer cell line BGC-823 Binds to 3' miR-16 in Bladder cancer cell line TCHu-1 UTR of CCND1 in gastric cancer. miR-365 Binding of miR16 to 3' UTR of CCND1 and its markedly decreased the expression (mRNA and reduced expression was validated by luciferase protein) of CCND1. Conversely, miR365 assay, while the reverse result was obtained by knockdown repressed cell growth, which can be mutation of the conserved miR-16 binding motif. overcome by CCND1 over-expression. Similar Overexpression of miR-16 in TCHu-1 cells led to inverse co-relation was obtained between miR-365 reduced CCND1 protein expression, whereas its and CCND1 expression in patient samples. (Long- inhibition led to an increased expression of CCND1 Guo et. al., 2013). (Jiang et. al., 2013). in Vascular smooth muscle cell (VSMC) miR-365 miR-9 in Gastric cancer Databases indicated suppresses CCND1 significantly in mRNA and potential binding site of miR-9 with high protein levels in primary rat VSMC. CCND1 is a complementarity at CCND1 39-UTR (bases 2974- direct target of miR-365 in vascular smooth muscle 2995), which was validated by luciferase reporter cells, as shown by significant inhibition of the assay. Significant inverse correlation between miR- luciferase activity of wild type CCND1 3' UTR, but 9 expression and CCND1 transcript levels in gastric not the mutant cyclinD1 3' UTR with the mutant cancer tissues and cell lines. Overexpression of biding site of miR-365 (Zhang et. al., 2014). CCND1 miR9 in gastric cancer cell lines SGC-7901 and AGS is a potential target of mir-365 through direct resulted in reduced RNA and protein expression of binding. (Kim et. al., 2014). CCND1, whereas knockdown of miR-9 produced in Colon cancer miRNA directly binds to the 3'UTR the opposite result, proving that miR-9 considerably of CCND1, proved by luciferase reporter assay. inhibited the expression of CCND1 through post- Transfection of miR365 significantly decreased transcriptional repression. Results validated by in- CCND1 expression in HT29 and LoVo cells. vitro experiments (Zheng et. al., 2013). Pearson's co-relation between miR-365 levels and miR-195 in Glioma Analysis using publicly CCND1 expression by qRT-PCR and western blot available algorithms (TargetScan, Pictar, showed that they were inversely correlated (Nie et. miRANDA) indicates that CCND1 is a predicted al., 2012). target of miR-195, which was validated by miR-338-3p in Hepatocyte cell line LO2 miR-338- overexpression of miR- 195, which reduced, but 3p binds at two regions in the 3' UTR of CCND1( inhibition of miR-195 increased, the luciferase mainly at the site spanning nucleotides 2397-2403). activity of CCND1-39UTR in a consistent and dose- Overexpression of miR-338-3p downregulates dependent manner. Upregulation of miR-195 endogenous CyclinD1 protein, while inhibition decreased, but inhibition of miR-195 increased, the upregulates CyclinD1 protein, without any change in expression levels of CCND1 in LN18 and T98G CCND1 mRNA levels. miR-338-3p post- glioma cells. The findings were also validated in a transcriptionally regulates CCND1 (Fu et. al., 2012). model system in mice (Hui et. al., 2013). miR-19a in Human umbilical vein endothelial miR-155 in Human extravillous trophoblast cells (HUVECs) miR-19a binding site (nucleotides derived HTR-8/SVneo cells Bioinformatics 1,778-1,785 in human CCND1) identified by analysis showed that, at the 3' untranslated region sequence alignment, which is highly conserved (UTR) of CCND1, six bases are complementary to among different species. Binding of miR-19a to 3' the seed region of miR-155. Luciferase assays and UTR of CCND1 verified by luciferase assay. CCND1 3'UTR transfection assays validated that CCND1 protein expression markedly reduced upon CCND1 3'UTR was the target of miR-155 in HTR- over-expression of miR-19a, although no change in 8/SVneo cells. Overexpression of miR-155 in HTR- RNA expression. miR-19a post-transcriptionally 8/SVneo cells reduced the level of CCND1 protein regulates CCND1 expression (Qin et. al., 2010). (Dai et. al., 2012). miR-490-3p in A549 Lung cancer cell line miR- miR-143 in Mesenchymal stem cells from the 490-3p binds to 3' UTR of CCND1. Over-expression bone marrow of male Fischer 344 rats Ectopic decreased the expression of CCND1, both at the expression of miR-143 also increased CCND1 in the RNA and protein levels (Gu et. al., 2014). native MSC as compared with scramble transfected cells .On the contrary, pre-treatment of AAMSC

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with miR-143 specific antagomir significantly miR-15a and miR16-1 in Osteosarcoma They bind abolished CCND1 expression (Lai et. al., 2012). to 3'-UTR of CCND1 and suppress transcription of miR-21 CCND1 (Cai et. al., 2012). in Mouse liver regeneration Cyclin D expression miR-138 in Nasopharyngeal carcinoma CCND1 is and G1 phase transition of hepatocytes after 2/3 PH a novel direct target of miR138. mRNA levels of depend on induced miR-21 expression. Knockdown CCND1 were inversely correlated with miR-138 of miR-21 impaired progression of hepatocytes into expression (Liu et. al., 2012). S phase of the cell cycle, mainly through a decrease miR-34a in A549 cell line Ectopic expression of in levels of cyclinD1 protein, but not Ccnd1 mRNA, miR-34a reduces both mRNA and protein levels of whereas increased miR-21 expression facilitated CCND1 by targeting the 3'-untranslated mRNA CCND1 translation in the early phase of liver region of CCND1 (Sun et. al., 2008). regeneration (Ng et. al., 2012). miR-29a in Breast cancer cell lines Over- in Renal cancer miR-21 controlled the expression of expression of miR29a down-regulation of CCND1 CCND1 through NFkB-dependent transcription and expression in MDA-MB-453 cells, whereas in mediated renal cancer cell proliferation by CCND1 MCF-10A cells with Mir-29a knockdown, CCND1 (Bera et. al., 2013). was up-regulated (Wu et. al., 2013). miR-520-b in Hepatoma cell lines miR520-b miR-7 in Colorectal cancer cell lines Over- directly targets the 3 'UTR of CCND1; proved by expression of miR-7 significantly decreased CCND1 dual luciferase reporter system. Down-regulation of expression (Xu et. al., 2014). protein levels of CCND1 occurred on over- miR-545 in Lung cancer miR-545 caused cell cycle expression of miR520-b in HepG2 and H7402 cells, arrest at the G0/G1 phase and induced cell apoptosis while the over-expression occurred on inhibition in in lung cancer cells by targeting CCND1. The effects miR520-b. Tumors in mice over-expressing of CCND1 down-regulated by miR-545 were similar miR520-b also showed lower CCND1 expression to those caused by siRNAs of CCND1 and over- (Zhang et. al., 2012). expression of CCND1 could abolish the miR-545- miR-193b in Melanoma TargetScan showed that induced inhibition of cell proliferation (Du et. al., miR193b binds to the 3'UTR of CCND1, which was 2014). proved by luciferase reporter assay. miR-193b over- miR-125b in Melanoma Cells over-expressing expression led to nearly 50% reduction in CCND1 miR-125b exhibited reduced expression of CCND1 mRNA and protein levels in Malme-3M cells than in (Nyholm et. al., 2014). control (Chen et. al., 2010). miR-147 in Colon and lung cancer cells. miR-17/20 in Breast cancer Levels of the miR-17- Transfection of miR147 led to down-regulation of 5p/miR-20a miRNA cluster were inversely CCND1 (Lee et. al., 2014). correlated to CCND1 abundance in human breast tumors and cell lines. miR 17/20 negatively regulates Implicated in the expression of CCND1 by binding to a conserved 3'UTR region (nucleotides 2,109-2,117) of the gene t(11;14)(q13;q32)/B-cell malignancies (Yu et. al., 2008). CCND1/ IgH miR-20 and miR106-a in Spermatogonial stem cells (SCC) They promote renewal at the post- Disease transcriptional level via targeting CCND1. The t(11;14) is mainly found in mantle cell Knockdown of CCND1 results in renewal of SCCs lymphoma; also in: B-prolymphocytic leukaemia, (He et. al., 2013). plasma cell leukaemia, splenic lymphoma with miR-503 in Endometrioid endometrial cancer villous lymphocytes; rarely in: chronic lymphocytic (EEC) Binds to 5' UTR of CCND1 and its leukaemia, multiple myeloma expression is inversely co-related with CCND1 in Prognosis EEC tissues and cell lines (Xu et. al., 2013). according to the disease. miR-449b in SW116 colon cancer stem cell Cytogenetics Transfecting pre-miR-449b and inhibiting miR-449b altered protein expression levels of CCND1 (Fang, Complex karyotypes. 2013). Hybrid/Mutated gene 5' CCND1 translocated on chromosome 14 near JH (junctions genes of IgH) and C in 3'.

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Fluorescence in situ hybridization (FISH) for identification of t(11;14)(q13;q32) chromosomal translocation in metaphase nuclei. Orange probe represents CCND1 (chromosome 11q13), green represents IGH (chromosome 14q32). Fusion signals representing translocations are encircled in white. Image courtesy Ghielmini et. al., 2009.

Abnormal protein follicular lymphomas (9 / 9), mucosa associated no fusion protein, but promoter exchange; the lymphoid tissue lymphomas (5 / 5) and reactive immunoglobulin gene enhancer stimulates the lymphoid tissues (Specht et. al., 2002). expression of CCND1. Biliary Intraepithelial Neoplasia Oncogenesis (BilIN) / Pancreatic Intraepithelial Overexpression of CCND1 accelerates the cell Neoplasia (PanIN) transit through the G1 phase (Williams et. al., 1993, Immunohistochemical expression of CCND1 was Williams et. al., 1994, Rimokh et. al., 1994, absent or focal in nonneoplastic epithelium of the Wlodarska et. al., 1994, de Boer et. al., 1997, bile ducts and the pancreatic ducts, and were Stilgenbauer et. al., 1998, Donnellan et. al., 1998, Li occasionally observed in BilIN-1 and PanIN-1 and et. al., 1999, Wlodarska et. al., 2004, Sander et. al., more frequently in BilIN-2/3 and PanIN-2/3. No 2008). significant difference was obtained between t(11;19)(q13;p13) CCND1/ FSTL3 expression of BilIN and PanIN in semi-quantitative analysis (Sato et. al., 2014). Found in a case of chronic lymphocytic leukaemia (Hayette et al., 1998). Bladder cancer tumors Acute Lymphoblastic Leukemia (ALL) Increased CCND1 levels were not correlated with OS with a pooled HR estimate, but were Routinely used ALL drugs: Routinely used drugs significantly correlated with progression-free failed to bind to CCND1 in in vitro docking studies survival (Ren et. al., 2014). Over-expression of Pin (Jayaraman et. al., 2014). X1 in T24 cells leads to greater than 2 fold increase Adrenocortical tumors (AC) in mRNA expression of CCND1 than in control cell, CCND1 was over-expression in 31.0% (13/42) in with similar results obtained by Western blotting. A AC tumors compared to 17.5 % (4/23) in normal significant correlation between the immune- adrenal samples. Similarly, mRNA of CCND1 was histochemical expression of PinX1 and CCND1 was significantly over-expressed in AC compared to also observed in the UCB tissues (Liu et. al., 2013). normal samples (Mitsui et. al., 2014). Ursane triterpenoid isopropyl 3-hydroxyurs-12-en- 28-oat (UA17) (Natural compound): Protein level of B cell neoplasia CCND1 was down-regulated in a dose-dependent Strong CCND1 mRNA over-expression was manner when treated with UA17or Cisplatin in detected in mantle cell lymphomas (23 of 23), hairy NTUB1 cells. Enhanced decrease of level of CCND1 cell leukemias (5 of 19), and multiple myelomas (7 when treated with a combination of Cisplatin + of 23) with particularly high levels in 2 of the latter UA17 (Lin et. al., 2014) Metformin: Treatment with cases. Intermediate CCND1 transcripts were metformin leads to reduction in expression of detected in multiple myeloma (5 / 23), hairy cell CCND1 in a dose-dependent manner. Metformin leukemia (7 / 19) Low of no CCND1 was detected in treatment also markedly reduced the expression of B -cell chronic lymphocytic leukemias (10 / 10), CCND1 in Human Bladder Tumor Xenografts in

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Nude Mice compared to control (Zhang et. al., (Chen et. al., 2014). Fenofibrate: Fenofibrate 2013). decreased the expression of CCND1 in a time and dose dependent manner in Triple negative breast Breast cancer cancer cells (Li et. al., 2014). Obatoclax analog SC- CCND1 induction of Dicer coordinates microRNA 2001: SC-2001 down-regulated CCND1 in TNBC biogenesis by its transcriptional targeting (Yu et. al., cell lines in a dose- dependent manner (Liu et. al., 2013). CCND1 overexpression is associated with 2014). longer DSS, but not recurrence-free survival, in Chronic Myeloid Leukemia tumors patients with breast cancer (Chung et. al., 2014). (CML) There was a statistically significant reverse relationship of CCND1 with tumor grade and both Resveratrol (Res) (Natural compound): Res reduced ER and PR hormone receptors (Mohammadizadeh expression of CCND1 in K562 cells (Siu et. al., et. al., 2013). CCND1 was one of the most frequently 2014). Quercetin (Natural compound): CML KBM7 altered genes in breast cancer (Wheler et. al., 2014). Cells demonstrated reduction in expression on Activation of Notch-1 signaling up-regulated CCND1 on treatment with quercetin ((Li et. al., expression of CCND1 through NF-kB (Li et. al., 2014). 2014). Acylglycerol kinase (AGK) over-expression Colorectal cancer led to concurrent increase in levels of CCND1 There was significant association between post- (Wang et. al., 2014). Over-expression led to menopausal hormone therapy (HRT) and CCND1 blockade of CCND1 expression via BCAS2 and negative-tumors, as well as significantly increased beta-catenin (Sengupta et. al., 2014). Enhanced risk in CCND1 positive tumours (Brändstedt et. al., expression of Vav1 led to the elevation of CCND1 2014). High height and weight was associated with and the progression of cell cycle (Du et. al., 2014). risk of CCND1 positive CRC in women. Increased CCND1 was frequently more positive in ER alpha hip circumference, high BMI, high WHR and high positive and Bmi1 positive breast tumors than ER waist circumference was associated with CCND1 alpha negative and Bmi1 negative groups (Wang et. positive tumours in men (Brändstedt et. al., 2013). al., 2014). Progesterone induced the assembly of a CCND1 over-expression was significantly transcriptional complex among AP-1, Stat3, PR, and associated with both poor OS, DFS, relatively older ErbB-2 at the CCND1 promoter, which functions as patients (over 60 years), T3,4 tumor invasion, N an enhanceosome to drive breast cancer growth positive and distant metastasis (Li et. al., 2104). (Flaqué et. al., 2013). Prolactin-induced protein Galectin-3 knockdown decreased the mRNA (PIP) silenced cells showed marked decrease in expression level of CCND1, whereas epirubicin CCND1 expression (Naderi et. al., 2014). Calcitriol significantly up-regulated their expression. (Natural compound): In calcitriol-treated cells, the Combined treatment effectively reduced the mRNA presence of antiestrogen ICI-182 down-regulated expression of CCND1 (Lee et. al., 2013). HMGCR CCND1 gene expression (Martinez et. al., 2014). expression was significantly associated with Euginol (Natural compound): Treatment of euginol expression of CCND1 (Bengtsson et. al., 2014). decreased CCND1 level 3 fold in MDA-MB-231 CoCl2: Treatment of COCl2 leads to dose-dependent cells and 20 fold in MCF7 cells compared to control decrease in expression of CCND1 and cell cycle (Sharif et. al., 2013). Fangchinoline (Fan) (Natural arrest (Lopez-Sanchez et. al., 2014). SW620-S and compound): Fan decreased the expression of TGF-b1: Fibroblasts induced by Colorectal cancer CCND1 both in the RNA and protein level (Wang et. cells, treated with SW620-S and TGF-b-1 separately al., 2014). Gallotannin (Natural compound): showed high expression of CCND1 (Rao et. al., Nanostring and qPCR data showed that CCND1 was 2014). exclusively downregulated on treatment with gallotannin in triple negative breast cancer (Zhao et. Diffuse large B-cell lymphoma al., 2014). 8-bromo-7-methoxychrysin (BrMC) A case of diffuse large B-cell lymphoma was (Natural compound): BrMC caused a described, which developed within a rectal tubular dose-dependent reduction of CCND1 in HER2/neu adenoma with low-graded dysplasia. The mass over-expressing breast cancer cells (Cao et. al., showed positive staining of CCND1 (Genovese et. 2014). Panepoxydone (Natural compound): CCND1 al., 2014). was down-regulated by dose-dependent treatment of Panepoxydone (Arora et. al., 2014). Thymus Esophageal cancer caramanicus extract (TCE) (Natural compound): CCND1 G870A polymorphism had no significant TCE led to reduction in expression of CCND1, either association with esophageal squamous cell alone or in combination with Vincristine (Mahani et. carcinoma (ESCC) or esophageal adenocarcinoma al., 2014). Tea polyphenols (Natural compound): (EADC) in Caucasian or the Asian populations. Tea polyphenols did not significantly alter the However, the comparison of A vs. G in CCND1 expression of CCND1 in breast cancer cell lines G870A showed significant differential susceptibility

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to esophageal cancer, suggesting that the CCND1 Hepatocellular Carcinoma G870A polymorphism has no association with CCND1 Ectopic expression of miR-184 led to down- esophageal cancer risk in ethnicity and histology, regulation of the SOX7 protein, resulting in up- respectively (He et. al., 2013). No significantly regulation of CCND1, cell proliferation and statistical differences between the two groups were tumorigenesis (Wu et. al., 2014). SOX7- observed in distribution of genotypes or alleles at overexpression inhibited cell growth by down- CCND1 807 (Jang et. al., 2013). regulating CCND1, which could be over-ridden by Fibrosarcoma ectopic expression of CCND1 and induction of KIOM-C (Natural compound): Treatment of SOX7. Over-expression of SOX7 suppressed tumor HT1080 human fibrosarcoma cells led to down- formation with down-regulation of CCND1 in vivo regulated expression of CCND1 compared to control (Wang et. al., 2014). Knockdown of TRIM24 led to (Kim et. al., 2014). decreased CCND1 expression (Liu et. al., 2014). KIF14 knockdown suppresses tumor cell growth Gastric cancer through decrease in levels of cyclins including Down regulation of CCND1 by ShCCND1 in NCI- CCND1 (Xu et. al., 2014). Knockdown of N87 cells showed significant inhibition of cell expression of SHC SH2-domain binding protein 1 proliferation, cell motility, clonogenicity, G1 arrest (SHCBP1) led to reduction in expression of CCND1 and apoptosis. Results were validated by in vivo (Tao et. al., 2013). 7. 3, 3'-Di-O-methyl ellagic studies in mice, suggesting the possibility of acid-4'-O-d-xylopyranoside (JNE2). JNE2 induced developing new gastric cancer therapies using down-regulation of expression of CCND1 in HepG2 lentivirus-mediated shRNA (Seo et. al., 2014). Odd- cells (Zhang et. al., 2014). Silybin (SIL) (Natural skipped related 1 (OSR1) suppressed the expression compound): Treatment of HepG2 cells with SIL led of CCND1 (Otani et. al., 2014). Knockdown of P115 to down-regulation of expression of CCND1 (Zhang led to reduction in expression of CCND1, whereas et. al., 2013). SL1122-37: SL1122-37 induced down- its over-expression led to up-regulation of CCND1 regulation of expression of CCND1 in PLC/ PRF/5 (Li et. al., 2013). Caudatin 3-O-D-cymaropyranosyl- HCC cells (Qin et. al., 2013). IBN-65 (1-benzyl-2- (1 4)--D-oleandropyranosyl-(1 4)--D- phenyl-3-(4-isopropyl)-benzyl-imidazolium cymaropyranosyl-(1 4) -D-cymaropyranoside chloride) : IBN-65 decreased levels of CCND1 in (CGII) (Drug): CGII induced down-regulation of Huh7 cells in Mouse model of HCC (Gopalan et. al., expression of CCND1 in a dose-dependent manner 2014). Sorafenib and YC-1 : Treatment with the in Gastric Cancer SGC-7901 Cells (Wang et. al., sorafenib and YC-1 combination led to a significant 2013) Tetramethypyrazine (TMP) (Natural reduction in CCND1 (Kong et. al., 2014). compound): Expression of CCND1 gradually Hepatoma decreased with increasing concentrations of TMP in Gastric cancer 7901 cells (Ji et. al., 2014). Over-expression of HA-FHIT inhibited the Resveratrol (Res) (Natural compound): Res reduced expression of CCND1 in the cells. In HepG2 cells expression of CCND1 (Yang et. al., 2013). which were transfected with a full-length CCND1 promoter-luciferase reporter, cotransfection with Glioma increasing quantities of FHIT plasmid DNA caused Expression of Alpha enolase (ENO-1) inhibited the a concentration-dependent inhibition of the expression of CCND1 (Song et. al., 2014). transcriptional activity of the CCND1 promoter (Ge Hairy Cell Leukemia et. al., 2014). CCND1 displayed nuclear staining at variable Lung Cancer intensities but with high specificity and accuracy in PAX6 down-regulation led to reduction in protein HCL biopsies, thus representing it as a valuable tool levels of CCND1 (Zhao et. al., 2014). Over- in the differential diagnosis of HCL and its mimics expression of Ubiquitin- conjugating enzyme E2C (Toth-Liptak et. al., 2014). (UBE2C) increased expression of CCND1 in L-78 Head and neck squamous cell and SC-1680 cells, as well as in tumor transplants in nude mice (Tang et. al., 2014). Met- F-AEA in carcinoma tumors combination with URB597 induced down-regulation Amplification, over-expression and translocation of of CCND1 and subsequent G0/ G1 cell cycle arrest CCND1 has been reported (Akervall et. al., 1997, (Ravi et. al., 2014). Up-regulation of decorin led to Akervall et. al., 2002, Utikal et. al., 2005, Sabbir et. significant decrease in expression of CCND1 (Liang al., 2006). However, expression of CCND1 did not et. al., 2013). The expression of CCND1 was change in post-therapy tumors compared to pre- significantly decreased upon knockdown of Claudin- therapy (Sarkar et. al., 2014). 2 in lung adenocarcinoma (Ikari et. al., 2014). Knockdown of JAM-A decreased protein levels of CCND1 (Zhang et. al., 2013). Tea polyphenols

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(Natural compound): Epigallocatechin gallate, Nasopharyngeal cancer epicatechin gallate and theaflavin reduced the No significant association was found between expression of CCND1 in benzo(a)pyrene-induced CCND1 G870A polymorphism and nasopharyngeal lung carcinogenesis in mice (Manna et al., 2009). carcinoma risk in total population meta-analysis. In Polydatin: PD suppressed expression of CCND1 in the subgroup meta-analysis by ethnicity, a negative A549 and NCI-H1975 lung cancer cell lines (Zhang association was shown in Caucasian subgroup, and et. al., 2014). no significant association in any genetic models Mantle Cell Lymphoma among Asians was observed (Li et. al., 2013). Decrease in expression of CCND1 by RNSi induced Indole-3-carbinol (I3C) : I3C induced G1 arrest by partial inhibition and reduced expression of AKT decreasing CCND1 expression (Chen et. al., 2013). and/or S6, which may in turn lead to decrease in Neuroblastoma NOXA mRNA levels (Dengler et. al., 2014). 85% CCND1 showed strong nuclear reactivity in a case were weakly positive and 15%, moderately positive study on Primary localized congenital with labelled streptavidin biotin, whereas 75% were sacrococcygeal neuroblastomas (SCNs) weakly positive and 25% moderately positive for (Khandeparkar et. al., 2013). Over-expression of n- CCND1 with EnVision. All 20 mantle cell myc downstream regulated gene 2 (NDRG2) lymphoma cases were strongly CCN D1 positive induced down-regulation of expression of CCND1 with catalyzed signal amplification. No evidence of (Zhang et. al., 2014). A negative co-relation existed CCND1 immunostaining was obtained in any of the between WWOX and CCND1 expression small lymphocytic lymphoma and follicular centre (Nowakowska et. al., 2014) cell lymphoma instances with any of the three methods used (Barranco et. al., 2003). CCND1 Odontogenic tumors showed exclusive nuclear staining and directly Using immune-labelling of CCND1, no statistical compared with the expression observed by difference was observed between primary and immunoblot analysis with the same antibody, as well recurrent KOT (keratocystic odontogenic tumors), as with mRNA expression and with the occurrence sporadic and NBCCS-KOT (nevoid basal cell of genomic rearrangements within the B CL-1 locus. carcinoma syndrome), and unicystic and solid AB 12/13 MCL showed over-expression by (ameloblastomas) (Gurgel et. al., 2014). immunohistochemistry or immunoblot, with similar results for additional 13 MCLs, indicating its Oral cancer importance for routine diagnostic purposes (Boer et. Expression of CCND1 in group 3 (leukoplakias al., 2014). CCND1 mRNA could be detected in 23 exhibiting dysplasias) was significantly higher than of 24 mantle-cell lymphomas by reverse in group 1 (normal buccal mucosa without any transcription polymerase chain reaction (RT-PCR) habits) and 2 (clinically normal mucosa from whereas only 9 of 24 demonstrated a t(11;14) by tobacco habits), expression in group 2 was PCR (Aguilera et. al., 1998). In 16 of 21 cases of significantly higher than in group and were MCL with overt disease, the ratio of CCND1 mRNA statistically significant. to 2-microglobulin mRNA was increased, but all 21 CCND1 was mostly expressed in the lower third of cases showed increased ratios of CCND1 mRNA to epithelium. Highest expression was obtained in mild CD19 mRNA (Howe et. al., 2004) dysplasias, with expression consistently correlating Melanoma with basilar hyperplasia among atypical morphological features (Ramakrishna et. al., 2013). Piperine (Natural compound): Piperine induced Clinico-pathological correlation showed that reduction in expression of CCND1 in a dose- CCND1 over-expression was related to increase in dependent manner in SK MEL 28 and B16 F0 tumor size, tumor differentiation and higher clinical melanoma cells (Fofaria et. al., 2014). stages and lymph node metastasis and adversely Multiple myeloma affected overall survival (Zhao et. al., 2014). HPV- CCND1 expression was observed in 57% cases. negative patients, heavy alcohol consumption was CCND1 positive group had significantly lower significantly associated with somatic copy-number hemoglobin level than CCND1 negative group, alterations (SCNAs) in CCND1 (Urashima et. al., though both groups showed no statistical 2013). significance in regard to age, gender, Durie and The proportions of positive staining in well, Salmon stage, lytic bone lesions, light chain moderately and poorly differentiated laryngeal SCC phenotype, creatinine, calcium, lactate were 50, 66.7, 100%, respectively, for CCND1, and dehydrogenase, leukocyte and platelet count and were statistically significant, with the expression bone marrow histology (Padhi et. al., 2013). being positively correlated with Ang-2 expression. Tumor grading and CCND1 were independent factors affecting laryngeal SCC patient survival by

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the Cox regression model of risk factors proportion other parameters. Thus, high CCND1 expression analysis, which may possess clinical significance in could be a potential marker for tumor aggressiveness evaluating the prognosis and guiding the clinical (Pereira et. al., 2014). Univariate analyses showed treatment of SCC (Liu et. al., 2013). Knockdown of that lymph node positivity, surgical margin Nemo-like kinases (NLK) led to significant positivity, non-localized tumor, age at prostatectomy reduction in the levels of CCND1 (Dong et. al., and CCND1 in malignant epithelium were 2013). 2,4-bis (p-hydroxyphenyl)-2-butenal : HPB significantly associated with time to BF 242 significantly decreased CCND1 expression in (Biochemical failure) (Rizzardi et. al., 2014). HN22 and HSC4 Oral squamous cell carcinoma cell Reevesioside A (Natural compound): Reevesioside lines (Chae et. al., 2014). A inhibited expression of CCND1 in Hormone- Osteosarcoma Refractory Prostate Cancers (Leu et. al., 2014). Scoparone (Natural compound): Scoparone Selective inhibition of Ether à go-go 1 (Eag1) led to suppressed the transcription of STAT3 target significant decrease in expression of CCND1 (Wu et. CCND1 in DU-145 cells (Kim et. al., 2013). al. 2014). Triptolide (Natural compound): Triptolide induced Ovarian serous carcinoma significant decrease of expression of CCND1 through EZH2 (Tamgue et. al., 2014). Pifithrin Compared with NOT (Normal Ovarian Tissue), (PFT) : Combination therapy with suboptimal doses CCND1 expression in the OSA (ovarian serous of PFT-m and HT decreased expression of CCND1 cystadenomas) and OSC (Ovarian serous carcinoma) (Sekihara et. al., 2013). groups was significantly elevated. Expression of CCND1 was positively associated with lymphatic Renal cancer metastasis and the expression gradually increased in Microvessicles: CCND1 protein expression in tumor the NOT, OSA, OS-BT and OSC groups and was tissues was markedly up-regulated by MVs released associated with tumor metastasis (Song et. al., 2014). from human Wharton's jelly mesenchymal stem cells Pancreatic cancer (hWJ-MSCs) (Du et. al., 2014). Silencing of Frizzled (Fz)2 by siRNA or shRNA Sarcoma induced significant reduction of expression on Tea polyphenol epigallocatechin gallate (EGCG) did CCND1 (Tomizawa et. al., 2014). Down-regulation not alter expression of CCND1 in Sarcoma180 cells of miR-196a led to decrease in expression of in vivo (Manna et. al., 2006) CCND1 via Nuclear Factor Kappa-B-Inhibitor Alpha (Huang et. al., 2014). Diallyl trisulfide T-cell Acute Lymphoblastic Leukemia (DATS) (Natural compound): DATS reduced levels Resveratrol (Res) (Natural compound): Expression of CCND1 and DATS-induced apoptosis was of CCND1 was attenuated in Res treated T-ALL correlated with down-regulation of CCND1 protein CEM-C1-15 cells (Ge et. al., 2013). levels in Capan-2 cells (Ma et. al., 2014). Uterine cervical cancer alpha-Mangostin (Natural compound): alpha-- Mangostin led to decrease in expression of CCND1 Bcl-1/Cyclin D1 alterations are associated with the (Xu et. al., 2014). Pristimerin (PM) : PM treatment development of uterine cervical carcinoma (Singh et. produced decreased expression of CCND1 in al., 2005). MiaPaCa-2 and Panc-1 cells (Deeb et. al., 2014). Various cancers Plasmacytoma Ursolic acid (UA) (Natural compound): UA in A solitary plasmacytoma following complete combination with other drugs led to down-regulation remission from an intravascular large B-cell of expression of CCND1 (Doudican et. al., 2014). lymphoma, stained strongly for CCND1 while the Salinomycin-: Salinomycin induced lowering of initial tumor was negative for CCND1, proving expression of CCND1 in Breast and prostate cancer different clonal origins of the tumors (Lee et. al., cells (Lu et. al., 2014). 2014). Non-cancerous tissues Prostate cancer Primary human cardiomyocytes: Thrombin time- CNCD1 staining was positive (expression in .5% of dependently up-regulated CCND1 expression, with tumor cells) in 64 cases (75.4%) and negative a significant response within 36-48 h (Chien et. al., (expression in 5% of tumor cells) in 21 cases 2014). (including 15 cases with no immunostaining) with Human diploid fibroblast (HDFs): CCND1 gene normal prostate tissues being negative for CCND1. was significantly up-regulated in irradiated (1 Gy) Patients with high grade Gleason score and HDFs as compared to untreated control, while perineural invasion showed significant association bothHDFs treated with Gelam honey and irradiated with CCND1 expression, but not with PSA levels or HDFs pre-treated with Gelam honey showed down-

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regulation of cyclin D1 gene as compared to dependent on Akt1 expression. Low expression of irradiated HDFs. HDFs treated with Gelam honey CCND1 and increased expression of Twist and Slug during radiation and post-irradiation however was observed in mammary tumors that had showed significant up-regulation of cyclin D1 gene metastasized to secondary sites (Wu et. al., 2014). as compared to untreated control (Ahmed et. al., Atherosclerosis in mice: The expression levels of 2014). CCND1 in smooth muscle cells were restrained by Human coronary artery smooth muscle cells CD59 and C-PC (C-phycocyanin) (Li et. al., 2013). (HCASMCs): FABP4 induced increase in Mouse pancreatic cancer: Embelin-treated mice expression of the downstream genes CCND1 showed significant inhibition in tumor growth, (Girona et. al., 2013). which was associated with reduced expression of Vascular smooth muscle cells: STS (sodium CCND1 (Huang et. al., 2014). tanshinone IIA silate) decreased the expression of Human umbilical cord mesenchymal stem cells cell cycle-associated protein, CCND1 (Wu et. al., (hUCMSCs) in nude mice: In mice treated with 2014). PDGF-induced CCND1 mRNA and protein hUCMSCs-LV-IL-21, Expression of cyclin-D1 was expression was inhibited by TGFb. PDGF-induced simultaneously low compared to control group, CCND1 expression requiring KLF5 was inhibited by hUCMSCs group and hUCMSCs-LV-Vec group TGFb via a Smad dependent mechanism, leading to (Zhang et. al., 2014). G1 cell cycle arrest of VSMs (Garrido et. al., 2013). Partial hepatectomy: Following seventy percent Neuroectodermal stem cells: PGE2 (Prostaglandin partial hepatectomy (PH) in wild type (WT) mice IL- E2) treatment significantly up-regulated CCND1 6 serum levels increased, resulting in increased (Wong et. al., 2014). CCND1 (Tachibana et. al., 2014). Neurons: DYRK1A (dual specificity tyrosine- Cow: phosphorylation-regulated kinase 1A) reduced Dairy Cow Mammary Epithelial Cells: Treatment cellular CCND1 levels by phosphorylation on with leucine induced LeuRS, increasing CCND1 Thr286, which is known to induce proteasomal mRNA and protein expression (Wang et. al., 2014). degradation (Soppa et. al., 2014). Rat: Renal intestinal fibroblasts: Exposure of NRK- Rat epithelial cells: CCND1 accumulation due to 49F to resulted in reduced expression proliferation differential effects of of PKC was likely contribute markers CCND1 in a dose and time dependent to the opposing tumor suppressive and tumor manner (Ponnusamy et. al., 2014). promoting activities in the intestinal epithelium Idiopathic pulmonary fibrosis (IPF): Cell cycle (Pyfz et. al., 2014). regulatory protein CCND1 was significantly Hyperbilirubinemic Gunn Rat: Decreased enhanced in AEC (alveolar epithelial cell) within the expression in CCND1 in the cerebellum of the remodelled fibrotic areas of IPF lungs but expression hyperbilirubinemic Gunn rats led to significant was negligible in myofibroblasts (Akram et. al., increased cell cycle arrest in the late G0/G1 phase 2014). (Robert et. al., 2013). Human Rheumatoid Arthritis Synovial Cells: Neonatal hypoxia-ischemia in rat: IGF-1R The protein and mRNA levels of CCND1 decreased activation together with EGFR co-signaling gradually with the increasing of thapsigargin decreased the percentage of cells in G1 and enhanced concentration and treatment times (Wang et. al., cell progression into S and G2 by increases in 2014). expression of CCND1 (Alagappan et. al., 2014). Rat balloon injury model: CCND1 mRNA was Other mammals significantly decreased by sodium ferulate in cells Mouse: under serum stimulation (Zhang et. al., 2014). Adult mice cardiomyocytes: Silencing the CCND1 Rat liver fibrosis: Sophocarpine inhibited the expression is necessary for the maintenance of the proliferation of HSCs by a decrease in the expression cell cycle exit, and suggests a mechanism that of CCND1 (Qian et. al., 2014). involves inhibition of M-phase entry (Tane et. al., Rat Airway Smooth Muscle Cells: Nicotine 2004). significantly increased expression of CCND1 (He et. Mouse hair follicle (HF): Real-time PCR analysis al., 2014). revealed an inverse relationship between CCND1 Chicken: expression pattern and that of Sfrp2 throughout the Chicken fetal myoblasts (CFMs): Increased HF cycle (Kim et. al., 2014). CCND1 expression during acceleration of cell cycle Mouse mammary gland: CCND1 was more at G1/ S phase in CMF was due to CARP (cardiac frequently up-regulated in mammary tumors from ankyrin repeat protein) over-expression (Ma. et. al., transgenic mice (expressing myristoylated-Akt1 2014). (myr-Akt1) under the control of the MMTV-LTR promoter) compared to tumors from wild-type mice. References Increased expression of CCND1 was incompletely

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Atlas Genet Cytogenet Oncol Haematol. 154 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Classification of myelodysplastic syndromes 2015 Virginie Eclache Laboratoire d'hématologie et de cytogénétique, Hôpital Avicenne, Bobigny, France virginie.eclache @avc.aphp.fr

Published in Atlas Database: April 2015 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ClassifMDSID1058.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62527/04-2015-ClassifMDSID1058.pdf DOI: 10.4267/2042/62527 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

(BM) with dysplasia, with or without excess of Abstract blasts. The Myelodysplastic syndromes are a heterogeneous Phenotype/cell stem origin group of hematological malignancies difficult to MDS is thought to result from the accumulation of diagnose and classify, for which novel treatments are genetic or epigenetic (such as promoter beginning to emerge. Recent advance in diagnosis hypermethylation) lesions, occurring initially in an classification, prognosis scoring and genetics immature progenitor and leading to a proliferative discovery are presented in this update. advantage of the MDS clone over normal immature Keywords progenitors. MDS progenitors display abnormal Myelodysplastic syndromes; Refractory Anemia terminal differentiation and increased susceptibility with excess blasts; Refractory Anemia with Ring to apoptosis. These two features explain the clinical sideroblasts; Refractory Cytopenia with Unilineage consequences of blast accumulation and peripheral Dysplasia; Refractory Cytopenia with Multilineage cytopenias (Mufti, 2004). Dysplasia; MDS-Unclassifiable; Etiology Thrombocytopenia; Neutropenia; Anemia Age-induced genetic, epigenetic, and immune- Note mediated changes in haemopoietic stem cells (HSC) This paper is an update of " Classification of lead to oligoclonal expansion of myelodysplastic myelodysplasic syndromes 1999 " (Flandrin, 2002). stem cells, with defective differentiation, characterised by increased apoptosis of erythroid and Clinics and pathology myeloid progenitors (Corey et al., 2007). Disease Microenvironmental changes and immune deregulation contribute to this differentiation defect. Myelodysplastic syndromes (MDS) are a Congenital bone marrow failure syndromes as heterogeneous group of clonal disorders of the Fanconi's anemia (FA), neurofibromatosis, hematopoietic stem cell (HSC) characterized by dyskeratosis, Down syndrome and familial platelet peripheral cytopenias despite increased disorder (associated with germ line mutations of hematopoïetic precursors, leading to transformation RUNX1 or CEBPa) predispose to MDS/ AML. into acute myeloid leukemia (AML) in 20-30% of cases (Mufti, 2004). Epidemiology Clinical manifestations result from cytopenias The median age at diagnosis is approximately 70 (anemia, infection, and bleeding). Diagnosis is based years. on blood cytopenias and hypercellular bone marrow

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Table 1: WHO classification for MDS (Vardiman et al. 2009)

The incidence is 4 to 5 per 100,000 persons per year. differential diagnoses (Kaloutsi V et al., The etiology is generally unknown, the role of 1994;Bennett et al., 2009). exposure to environmental chemical and physical Presence of dysplasia is the first key criterion for mutagens is sometimes suspected. In 15 to 20% of diagnosis and prognosis of MDS. cases, however, MDS are secondary (sMDS) to A given lineage is considered dysplastic if two or chemotherapy and/or radiotherapy for a prior illness, more dysplastic features are found on > 10% cells. usually cancer. More rarely, they are secondary to Multilineage dysplasia (MD) is defined as the exposure to benzene or other aromatic hydrocarbons, coexistence of dysplasias in two or more lineages. or products used in agriculture. Blast excess is frequent in MD but 40-60% of cases occur without blast excess. Cytology The term idiopathic cytopenias of undetermined MDS have received a variety of nomenclatures, until signification (ICUS) has been coined to account for the first international classification by the French cases when differential diagnoses have been American British (FAB) group in 1982 (Bennett et excluded, but cytopenias or dysplasias do not reach al., 1982). This classification has been refined in significant MDS diagnostic thresholds. The outcome 2001 then in 2008 by a WHO expert committee of ICUS still remains undetermined, but probably (Vardiman et al, 2002; and 2009), integrating novel evolves sometimes into MDS, and thus requires prognostic factors in MDS, such as multilineage blood and BM monitoring (Wimazal et al., 2007). dysplasia. The marrow blast threshold of AML was Ringed sideroblasts (RS), ie. sideroblasts with ? 5 lowered from 30% to 20%. This classification also siderophilic granules contouring at least a third of the designed the term MDS/MPN (Myeloproliferative nucleus circumference, are not specific of MDS as Neoplasm) to regroup a heterogeneous set of rare they can be encountered in a variety of conditions entities including chronic myelomonocytic leukemia such as alcohol consumption, copper deficiency or (CMML), previously considered as a MDS. zinc excess, as well as a rare congenital condition Three minimal criteria must be met for the diagnosis called X recessive sideroblastic anemia. RS are of MDS: 1) persistent (> 6 months) and significant considered significant when they represent > 15% of cytopenia(s) (Hb < 10 g/dL, absolute neutrophil erythroid cells. However, in the absence of blast count < 1.8 G/L, platelets < 100 G/L), 2) significant excess, RS define an entity with favourable bone marrow dysplasia, or blast excess or typical prognosis, termed refractory anemia with ringed cytogenetic abnormality, and 3) exclusion of sideroblasts (RARS).

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Table 2a: Karyotype (IPSS-R) - AML =acute myeloid leukaemia. NR = not reached.

Auer rods have historically been recognized as a dubbed "abnormally localized immature myeloid poor prognostic marker and remain considered in the progenitors" (ALIP). ALIP have been proposed as WHO classification. diagnostic and prognostic markers. Some morphologies can be strongly evocative of a Immunohistochemistry with a CD34 antibody marks precise underlying cytogenetic or genetic aberration. immature hematopoietic progenitors and For instance, a characteristic dysgranulopoiesis megakaryocytes, and can be used to asses the blast combining pseudo-Pelger-Huüt anomaly and small percentage. vacuolated neutrophils has been associated with 17p However, some MDS have CD34- blasts in MDS: in deletions and TP53 tumour suppressor gene those cases, CD117 has been proposed as a surrogate mutations (Lai et al., 1995). The "5q- syndrome" marker. which was recognized in 2001 by the WHO Some authors have proposed that the presence of classifications also has a distinct morphology. CD34+ cell clusters may better reflect prognosis Precise count of BM blasts is the second central than CD34+ cell percentage. criterion for diagnostic and prognostic classification of MDS. Myeloblasts are consensually defined by a Treatment high nuclear/cytoplasmic ratio and diffuse chromatin Treatment varies from symptomatic treatment of pattern, can be "agranular" or "granular". A third cytopenias, especially by transfusions for anemia, to class of blasts defined by the presence of numerous allogeneic stem-cell transplantation. Treatment of (>20) azurophilic granules is included in the blast patients with lower-risk myelodysplastic syndromes percentage, and can be distinguished from includes growth factors and lenalidomide. Higher- promyelocytes by the lack of Golgi structure (Mufti risk patients are treated with hypomethylating agents et al., 2008) and, allogeneic stem-cell transplantation whenever Pathology possible (Fenaux et al. 2009). BM biopsy first allows objective evaluation of BM Evolution cellularity, which physiologically declines with age. Progression to acute myeloid leukaemia depends on Application of a standardized age correction to prognosis factors. Rare cases progress to aplastic cellularity brings the incidence of "hypoplastic" anemia. MDS from 29% to 7% (Thiele et al., 2005). Hypoplastic MDS raises the question of the Prognosis differential diagnosis with aplastic anemia (AA). Prognostic evaluation in MDS still largely relies on Features of MDS are the presence of circulating an International Prognostic Scoring System (IPSS) myeloblasts, megakaryocytic or granulocytic established on the basis of an international cohort of dysplasia. Mild erythroid dysplasia can be seen in patients (IMRAW cohort) treated symptomatically AA. Other MDS criteria include abnormal and recently revised (IPSS-R) (Greenberg et al, sideroblasts, presence of two or more blast cell 1997; and 2012). IPSS relies on number of clusters. Clusters (3-5 cells) or aggregates (> 5 cells) cytopenias, marrow blast percentage and of blasts cells away from endosteal or vascular cytogenetic. Patients are regrouped into four risk niches, in the central portion of the BM, have been categories (low, intermediate 1 and 2, and high).

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Table 2b: IPSS-R Prognostic Score Values - ANC: Absolute neutrophil count, BM: bone marrow

Table 2 c: IPSS-R Prognostic risk Categories/Scores

The IPSS has since been validated in many abnormal in 35-40% of patients by conventional therapeutic contexts including intensive banding karyotyping, and cytogenetic aberrations chemotherapy and allogeneic stem cell are highly heterogeneous. transplantation (ASCT). IPSS categories are often Abnormal karyotype, especially those of regrouped into lower-risk MDS (IPSS low and unfavourable prognosis, are more frequent in cases intermediate-1), and higher-risk MDS (IPSS with blast excess, with 75% RA presenting with intermediate-2 and high). Lower-risk MDS are Normal karyotype (NK), compared to 25-50% patients with prolonged survival where the main abnormal karyotype in RAEB1-2, or secondary objectives are to cope with chronic cytopenias MDS (80% versus 40% in de novo MDS). notably anaemia, and to defer ASCT. On the other The most frequent types of abnormalities by hand the treatment in higher-risk MDS should alter frequency order are total or partial chromosome disease history and prolong survival. The approval losses, total or partial chromosome gains, and of azacytidine in higher-risk underscores the unbalanced translocations. Balanced translocations importance of IPSS evaluation in all patients at are rare. diagnosis. Frequent alterations represent 40% of all abnormal According to the IPSS-R, 27% of the lower-risk karyotypes, including partial or total deletion of MDS patients of the original IPSS are reclassified as chromosome 5 (?5/5q?), partial or total deletion of having a higher risk and they potentially need a more chromosome 7 ( -7/del(7q)), trisomy 8 (+8), partial intensive treatment. Conversely18% of high-risk deletion of chromosome 20 (del(20q)), and Y MDS patients, as defined by the original IPSS, are chromosome loss (?Y). These last alterations are not reclassified as low risk by the IPSS-R. specific of MDS and can be encountered in AML or in myeloproliferative neoplasm. Loss of Genetics chromosome Y can be found in elderly healthy subjects (Wiktor et al, 2000). Trisomy 8 and loss of Clonality assays based on gene imprinting Y may be present in a constitutional mosaicism. (HUMARA assays) have historically been the first Thus a constitutional karyotype on blood sample molecular tools to confirm the clonal nature of cultivated with phytohemaglutin as mitogen can be normal karyotype MDS. They still can serve as performed in those two cases for correct diagnostic co-criterion, but novel genomic tools are interpretation of cytogenetic response after intensive now available that can both confirm clonality and therapy or transplantation. provide valuable prognostic information. (Bejar R et Chromosome 5 and 7 alterations and other al 2011) infrequent alterations in AML are considered as "myelodysplasia related changes" in the current Cytogenetics WHO classification, as they may reflect an underlying undiagnosed myelodysplasia. The Cytogenetics morphological remaining 60% of abnormal karyotype display rare Conventional cytogenetic in de novo MDS is alterations

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Del5q and the "5q- syndrome" toxic exposure. It is the most frequent alteration in Interstitial deletion of the long arm of chromosome childhood MDS where it is often accompanied by a 5 (del(5q)), is the most frequent cytogenetic degree of myeloproliferation. There also is in vitro aberration in MDS, occurring in 15% of patients. evidence that G-CSF treatment may select a -7 clone, The "5q- syndrome" first described by Van den and that 7q is a genetically instable region. Patients Berghe in 1974, is characterized by an isolated with -7/del(7q) have neutrophil functional del(5q) and absence of PB or BM blast excess, and impairment, and thus may present severe infections is now part of WHO classifications (Vardiman et al, despite moderate neutropenia. 2008). Isolated del(5q) is favourable in the IPSS. The Those patients poorly respond to intensive distinct morphologic features of 5q- syndrome chemotherapy but interesting results have been include thrombocytosis in a third of patients, described with ypomethylating agents (Fenaux et al., macrocytic anemia, and hypolobulated 2009). megakaryocytes, contrasting with little dysplasia 3q26 abnormalities along the granulomonocytic and erythroid lineages. Other reputed pejorative abnormalities considered in The erythroid lineage may often be hypoplastic. the IPSS-R include the 3q26 alterations Prognosis is favourable, with a prolonged overall inv(3)(q21q26), and t(3;3)(q21;q26) that rearrange survival and a low risk of progression to AML. the MECOM (MDS1/EVI1) locus with complex Clonal evolution is also rare without treatment. The oncogenic roles and may be associated with prognosis is in fact dominated by the consequences thrombocytosis. Numerous other partners of EVI1 of chronic transfusions, but these patients are known as PRDM16 in t(1;3)(p36;q21) and dramatically respond to the immunomodulatory RUNX1 in t(3;21)(q26;q22). agent lenalidomide, with two thirds reaching long- 17p- / -17 and TP53 mutations term transfusion independency (Raza et al, 2008). 17p deletion, monosomy 17, unbalanced The 5q deletion is variable in size, but invariably translocation or isochromosome 17 which involve affects the q31 to q33 bands. A common 5q33 the loss of one TP53 locus are found mainly in deletion spanning over 1.5 Mb and encompassing 42 sMDS/AML after chemotherapy and/or genes has been delineated. The lack of recurrent radiotherapy, usually in association with other point mutation or of cryptic deletion on the normal complex chromosomal anomalies. There is an 5q allele supports an haploinsufficiency model association between vacuolated pseudo-Pelger-Huet whereby loss of a single copy of one or more granulocytes and chromosome 17p deletion with probably several genes cause 5q syndrome. Several consistent involvement of TP53 gene located at candidate genes have been implicated including 17p13. It occurs in MDS and AML with poor SPARC, CTNNA1, EGR1, and RPS14. prognosis. Some reports pinpoint the strong Haploinsufficiency for the ribosomal subunit RPS14 association of TP53 mutations and 5q deletion in induces a P53-dependent block in erythroid MDS (Jädersten et al, 2011). proliferation and differentiation, whereas Others abnormalities haploinsufficiency of two micro-RNAs, MIR145 Other favourable aberrations in the IPSS include and MIR146a, leads to dysmegakaryopoiesis and del(20q) which is not specific of MDS, and has been thrombocytosis (Ebert et al, 2008). associated with a specific presentation involving Patients with blast excess or additional cytogenetic frequent thrombocytopenia. aberrations can also harbour del(5q) but the Recurrent unbalanced translocations involving 1q prognosis is much more unfavourable than 5q- have been found in primary MDS with a partial syndromes. trisomy for the long arm of chromosome 1. Such Trisomy 8 rearrangements are described as t(1;15)(q11;p11); Trisomy 8 +8, (10-15%) that sometimes results from t(Y;1)(q12;q12), der(16) t(1;16)(q11;q11). In germinal mosaicism, is often subclonal, fluctuating secondary MDS translocation with the long arm of independently of blast counts. This suggests it is a chromosome 7 is not rare. secondary lesion in MDS. Deletion 9q, del(11q), del(12p) and del(13q) are Monosomy 7 / deletion 7q recurrent in MDS. MDS presenting with deletion of Chromosome 7 anomalies including del(7q), the short arm of chromosome 12, del(12p) are monsomy 7 (-7/del(7q)), or more rarely t(1;7), are heterogeneous. Association with multiple karyotypic second in frequencies after del(5q) (10%) and have changes in sMDS is more common than de novo almost invariably been assigned a poor prognostic disorders with a 12p- chromosome as a sole value in terms of both survival and transformation aberration. Deletions are usually interstitial, with risk. Different minimal regions of deletion have been loss of material between band p11 and p13. FISH described in 7q35-36, possibly with distinct method has been used to show that both ETV6 and prognostic values. Monosomy 7 can transform the gene for an inhibitor of a G1 cyclin-dependant constitutional bone marrow failures syndromes (FA, protein kinase (CDKN1B) are deleted in all myeloid Down syndrome) or AA, or arise after radiation or

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malignancies with a del(12p) including MDS Over expression of the EVI1 gene is found in one (Haferlach et al, 2011). third of MDS patients, particularly those with blast Acquired monosomy X has been sporadically found excess, even without 3q26 rearrangement in in female MDS patients. Xq13 may also be involved conventional cytogenetic. in translocations in MDS, as well as in As in AML, the WT1 transcription factor is also over rearrangements such as an isodicentric chromosome expressed in virtually all cases of MDS with blast X with breakpoint at q13 (idic(X)(q13)). excess, but also in a third of lower-risk MDS. The Complex karyotypes leukemogenic potential of this lesion is still unclear, Complex karyotypes (15%) are conventionally but its over expression can provide a tool for minimal defined as the coexistence of at least 3 anomalies that residual disease (MRD) monitoring in the context of are thought to result from alterations in DNA repair intensive therapy, like in AML. or checkpoint signalling. Complex karyotypes are by essence heterogeneous, with a prognosis worsening References with each additional aberration, rather than by the Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, chromosomes involved (most frequently, 5, 7 and Garcia-Manero G, Kantarjian H, Raza A, Levine RL, 17). Complex karyotypes are highly chemoresistant, Neuberg D, Ebert BL. Clinical effect of point mutations in but interesting results with the hypomethylating myelodysplastic syndromes. N Engl J Med. 2011 Jun agent decitabine have been observed, that need to be 30;364(26):2496-506 confirmed on larger cohorts. Bennett JM, Orazi A. Diagnostic criteria to distinguish Rare translocations hypocellular acute myeloid leukemia from hypocellular t(2;11)(p21;q23) implicate miR- myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. 125b1;t(6;9)(p22;q34) leads to DEK/NUP214 Haematologica. 2009 Feb;94(2):264-8 fusion. Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC, Clonal evolution Schimmer AD. Myelodysplastic syndromes: the complexity New rearrangements frequently occur, with disease of stem-cell diseases. Nat Rev Cancer. 2007 Feb;7(2):118- progression. Limited data is available on the 29 prognostic value of clonal evolution, but it is Damm F, Kosmider O, Gelsi-Boyer V, Renneville A, generally considered pejorative, as higher-risk Carbuccia N, Hidalgo-Curtis C, Della Valle V, Couronné L, aberrations appear. Scourzic L, Chesnais V, Guerci-Bresler A, Slama B, Beyne- Rauzy O, Schmidt-Tanguy A, Stamatoullas-Bastard A, Dreyfus F, Prébet T, de Botton S, Vey N, Morgan MA, Cross Genes involved and NC, Preudhomme C, Birnbaum D, Bernard OA, Fontenay M. Mutations affecting mRNA splicing define distinct clinical proteins phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood. 2012 Apr Note 5;119(14):3211-8 Somatic mutations are observed in approximately Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, 80% of the MDS (Bejar et al, 2011). The most Raza A, Root DE, Attar E, Ellis SR, Golub TR. Identification common genes are those involved in epigenetic of RPS14 as a 5q- syndrome gene by RNA interference regulation (TET2 , ASXL1, EZH2, DNMT3A, screen. Nature. 2008 Jan 17;451(7176):335-9 IDH1, IDH2 (Kosmider et al, 2009), splicing Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli (SF3B1, correlated to RARS, SRSF2, U2AF35, C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, ZRSR2)( Damm et al, 2012), transcription (RUNX1 Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR. , ETV6, CBL, NRAS , KRAS, NF1, PTPN1, TP53) Efficacy of azacitidine compared with that of conventional and less often cohesin genes. TP53 mutated care regimens in the treatment of higher-risk subclones may occur at early disease stage in MDS myelodysplastic syndromes: a randomised, open-label, with del(5q) where they are associated with a lower phase III study. Lancet Oncol. 2009 Mar;10(3):223-32 response to lenalidomid and an increases risk of Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz progression. (Jädersten et al, 2011). G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, It has recently been described that approximately Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic half of RARS with thrombocytosis (RARS-T) syndromes. Blood. 1997 Mar 15;89(6):2079-88 patients, along with a small subset of other MDS and mixed myelodysplastic/ myeloproliferative Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia- V617F Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, disorders, carry the JAK2 mutation, and Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, scarcely MPL mutations. RARS-T patients show Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak clinical features of both RARS, essential ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, thrombocytemia and to some extent myelofibrosis. Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, However, the degree of anaemia and overall survival Germing U, Haase D. Revised international prognostic is more similar to RARS than to myeloproliferative scoring system for myelodysplastic syndromes. Blood. 2012 disorders (Hellström-Lindberg et al., 2008) Sep 20;120(12):2454-65

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Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger Sanz G, Tomonaga M, Vallespi T, Yoshimi A. Diagnosis and T, Hildebrandt B, Kundgen A, Lübbert M, Kunzmann R, classification of myelodysplastic syndrome: International Giagounidis AA, Aul C, Trümper L, Krieger O, Stauder R, Working Group on Morphology of myelodysplastic Müller TH, Wimazal F, Valent P, Fonatsch C, Steidl C. New syndrome (IWGM-MDS) consensus proposals for the insights into the prognostic impact of the karyotype in MDS definition and enumeration of myeloblasts and ring and correlation with subtypes: evidence from a core dataset sideroblasts. Haematologica. 2008 Nov;93(11):1712-7 of 2124 patients. Blood. 2007 Dec 15;110(13):4385-95 Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Haferlach C, Bacher U, Kohlmann A, Schindela S, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg Alpermann T, Kern W, Schnittger S, Haferlach T. CDKN1B, PL, Curtin PT, Klimek VM, Shammo JM, Thomas D, Knight encoding the cyclin-dependent kinase inhibitor 1B (p27), is RD, Schmidt M, Wride K, Zeldis JB, List AF. Phase 2 study located in the minimally deleted region of 12p abnormalities of lenalidomide in transfusion-dependent, low-risk, and in myeloid malignancies and its low expression is a intermediate-1 risk myelodysplastic syndromes with favorable prognostic marker in acute myeloid leukemia. karyotypes other than deletion 5q. Blood. 2008 Jan Haematologica. 2011 Jun;96(6):829-36 1;111(1):86-93 Hellström-Lindberg E, Cazzola M. The role of JAK2 Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt mutations in RARS and other MDS. Hematology Am Soc J, Orazi A. European consensus on grading bone marrow Hematol Educ Program. 2008;:52-9 fibrosis and assessment of cellularity. Haematologica. 2005 Aug;90(8):1128-32 Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A, Van den Berghe H, Cassiman JJ, David G, Fryns JP, Hellström-Lindberg E, Mufti GJ. TP53 mutations in low-risk Michaux JL, Sokal G. Distinct haematological disorder with myelodysplastic syndromes with del(5q) predict disease deletion of long arm of no. 5 chromosome. Nature. 1974 Oct progression. J Clin Oncol. 2011 May 20;29(15):1971-9 4;251(5474):437-8 Kaloutsi V, Kohlmeyer U, Maschek H, Nafe R, Choritz H, Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz Amor A, Georgii A. Comparison of bone marrow and MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg hematologic findings in patients with human E, Tefferi A, Bloomfield CD. The 2008 revision of the World immunodeficiency virus infection and those with Health Organization (WHO) classification of myeloid myelodysplastic syndromes and infectious diseases. Am J neoplasms and acute leukemia: rationale and important Clin Pathol. 1994 Feb;101(2):123-9 changes. Blood. 2009 Jul 30;114(5):937-51 Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle Wei S, Chen X, Rocha K, Epling-Burnette PK, Djeu JY, Liu V, Picard F, Viguié F, Quesnel B, Beyne-Rauzy O, Solary Q, Byrd J, Sokol L, Lawrence N, Pireddu R, Dewald G, E, Vey N, Hunault-Berger M, Fenaux P, Mansat-De Mas V, Williams A, Maciejewski J, List A. A critical role for Delabesse E, Guardiola P, Lacombe C, Vainchenker W, phosphatase haplodeficiency in the selective suppression Preudhomme C, Dreyfus F, Bernard OA, Birnbaum D, of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci U Fontenay M. TET2 mutation is an independent favorable S A. 2009 Aug 4;106(31):12974-9 prognostic factor in myelodysplastic syndromes (MDSs). Blood. 2009 Oct 8;114(15):3285-91 Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K, Van Dyke DL. Clinical significance of Y chromosome loss Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke in hematologic disease. Genes Chromosomes Cancer. M, Lepelley P, Wattel E, Fenaux P. Myelodysplastic 2000 Jan;27(1):11-6 syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a Wimazal F, Fonatsch C, Thalhammer R, Schwarzinger I, high incidence of P53 mutations. Leukemia. 1995 Müllauer L, Sperr WR, Bennett JM, Valent P. Idiopathic Mar;9(3):370-81 cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface. Leuk Res. 2007 Mufti GJ. Pathobiology, classification, and diagnosis of Nov;31(11):1461-8 myelodysplastic syndrome. Best Pract Res Clin Haematol. 2004 Dec;17(4):543-57 This article should be referenced as such: Mufti GJ, Bennett JM, Goasguen J, Bain BJ, Baumann I, Eclache V. Classification of myelodysplastic syndromes 2015. Atlas Genet Cytogenet Oncol Haematol. 2016; Brunning R, Cazzola M, Fenaux P, Germing U, Hellström- 20(3):155-161. Lindberg E, Jinnai I, Manabe A, Matsuda A, Niemeyer CM,

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Leukaemia Section Short Communication t(11;19)(q13;p13) FSTL3/CCND1 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Published in Atlas Database: February 2015 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1119q13p13FSTL3-CCND1ID1527.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62528/02-2015-t1119q13p13FSTL3-CCND1ID1527.pdf DOI: 10.4267/2042/62528 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract function. FSTL3 Review on t(11;19)(q13;p13) FSTL3/CCND1, with data on clinics, and the genes involved. Location 19p13.3 Keywords t(11;19)(q13;p13); FSTL3; CCND1; chronic Protein lymphocytic leukemia Binds activin A and with lower affinity several other members of the TGF beta family; interacts with Clinics and pathology ADAM12, FN1 (fibronectin type 1,), and MLLT10 (Grusch, 2012). Disease B-cell chronic lymphocytic leukemia (B-CLL) Result of the chromosomal Epidemiology anomaly Only one case to date, a 67 year-old female patient (Rimokh et al., 1993; Hayette et al., 1998). Hybrid gene Prognosis Description The breaks occurred at nucleotide 2276 in the 3' No data untranslated region of the last CCND1 exon, and Cytogenetics about 7 kbp upstream of FSTL3. Cytogenetics morphological References Complex karyotype. Grusch, M. FSTL3 (follistatin-like 3 (secreted glycoprotein)) Atlas Genet Cytogenet Oncol Haematol. 2013;17(3):151- Genes involved and 154. Hayette S, Gadoux M, et al.. FLRG (follistatin-related gene), proteins a new target of chromosomal rearrangement in malignant blood disorders. Oncogene. 1998 Jun 4;16(22):2949-54. CCND1 Rimokh R, Berger F, et al.. Rearrangement and Location overexpression of the BCL-1/PRAD-1 gene in intermediate lymphocytic lymphomas and in t(11q13)-bearing leukemias. 11q13.3 Blood. 1993 Jun 1;81(11):3063-7. Protein Binds and activates the G1 cyclin dependent kinases; This article should be referenced as such: Phosphorylates SMAD3 and inhibits its Huret JL. t(11;19)(q13;p13) FSTL3/CCND1. Atlas Genet transcriptional activity and antiproliferative Cytogenet Oncol Haematol. 2016; 20(3):162-.

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Case Report Section Short Communication

The t(2;12)(p12;p13), leading to the juxtaposition of the cyclin D2 CCND2 gene with the immunoglobulin kappa locus (IGK), defines a small subset of mantle cell lymphomas lacking cyclin D1 expression. Nicolas Duployez, Laurent Pascal, Judith Bruge, Marie Fatoux, Catherine Roche-Lestienne Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU, Avenue E Avinée, 59037 Lille, (ND, CRL); Service d'Onco-Hématologie, GHICL Hopital St Vincent de Paul, Bd de Belfort, 59020 Lille, (LP) France; Laboratoire de Biologie, GHICL, Rue du Grand But B.P. 249, 59462 Lomme Cedex, (JB, MF) France. [email protected]; [email protected]; [email protected]; [email protected]; [email protected]

Published in Atlas Database: February 2015 Online updated version : http://AtlasGeneticsOncology.org/Reports/t0212p12p13DuployezID100081.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62529/02-2015-t0212p12p13DuployezID100081.pdf DOI: 10.4267/2042/62529 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Bone marrow : Bone marrow involvement (stage Clinics IV Ann Arbor). Age and sex Note 89 years old female patient. Rapid progression of the disease because 6 months Previous history ago laboratory analyses were normal (notably blood no preleukemia count). no previous malignancy no inborn condition of note Cyto-Pathology Organomegaly Classification No hepatomegaly, splenomegaly (moderate), enlarged lymph nodes, no central nervous system Phenotype: NA involvement Immunophenotype lymphoma cells CD19+ CD5+ CD20+ (strong), Blood CD22+ (strong), CD23+, FMC7+, monotypic kappa light-chain expression (moderate); Matutes score = WBC : 144 (lymphoma cells : 93%) Morphology 2/5. showed small to medium sized lymphoid cells with Rearranged Ig Tcr pale cytoplasm and slightly to markedly irregular Not performed. nuclear contour, sometimes mimicking centrocytes. Nucleoli were inconspicuous or absent.X 109/l Pathology HB : 12.8g/dl Mantle cell lymphoma Platelets : 196X 109/l Electron microscopy Blasts : NA Not performed.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3) 163 The t(2;12)(p12;p13), leading to the juxtaposition of the cyclin Duployez N, et al. D2 CCND2 gene with the immunoglobulin kappa locus (IGK), defines a small subset of mantle cell lymphomas lacking cyclin D1 expression.

Diagnosis Other Molecular Studies Mature B-cell neoplasm, cyclin D1-negative mantle cell lymphoma. Technics: CCND1 (BCL1) expression evaluated by RT-PCR. Survival Results: Date of diagnosis: 10-2014 No CCND1 overexpression. Treatment 10/2014: Patient first received chloraminophene and rituximab (2 courses). 12/2014: Patient was then treated with ibrutinib (140 mg x 4/day). Complete remission : no Treatment related death : no Relapse : no Status: Dead Last follow up: 01-2015 Survival: 4 months Partial GTG-banding karyotype of the t(2;12)(p12;p13). Karyotype Sample: Bone marrow Culture time: 96h DSP30/IL2 Banding: GTG Results 45,XX,t(2;12)(p12;p13),add(9)(p13),add(11)(q23),- 22[7]/46,XX[7] Other molecular cytogenetics technics FISH Other molecular cytogenetics results 45,XX,t(2;12)(p12;p13). ish der(2)t(2;12)(WCP12p+), der(12)t(2;12)(WCP12p+)[2]. FISH analysis of the t(2;12)(p12;p13)translocation, using painting probe of the short arm of chromosome 12 (WCP12p probe)in green. Arrows indicate the der(2) and der(12) chromosomes.

FISH analysis of the t(2;12) translocation, using BAC probe CCND2 RP11-264F23 in red and BAC probe RP11-530J6 located at 2q33 in green. Figure 3A is a normal metaphase and Figure 3B revealed the der(2) chromosome harboring CCND2 red signal.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(3) 164

The t(2;12)(p12;p13), leading to the juxtaposition of the cyclin Duployez N, et al. D2 CCND2 gene with the immunoglobulin kappa locus (IGK), defines a small subset of mantle cell lymphomas lacking cyclin D1 expression.

Leukemic phase of mantle cell lymphoma. Peripheral blood. Small to medium sized lymphoid cells with pale cytoplasm and slightly too markedly irregular nuclear contour, sometimes mimicking centrocytes. From a patient with 46,XX,t(2;12)(p12;p13).

Fu K, Weisenburger DD, Greiner TC, Dave S, Wright G, Comments Rosenwald A, Chiorazzi M, Iqbal J, Gesk S, Siebert R, De Jong D, Jaffe ES, Wilson WH, Delabie J, Ott G, Dave BJ, According to the WHO classification of Sanger WG, Smith LM, Rimsza L, Braziel RM, Müller- hematopoietic tumours, mantle cell lymphoma Hermelink HK, Campo E, Gascoyne RD, Staudt LM, Chan (MCL) is defined as a B-cell neoplasm composed of WC. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. monomorphic small to medium-sized lymphoid cells Blood. 2005 Dec 15;106(13):4315-21 with a CCND1 (cyclin D1) translocation. In recent years, it has been observed a small subset of Salaverria I, Royo C, Carvajal-Cuenca A, Clot G, Navarro A, Valera A, Song JY, Woroniecka R, Rymkiewicz G, lymphomas resembling conventional MCL both Klapper W, Hartmann EM, Sujobert P, Wlodarska I, Ferry morphologically and phenotypically, with a similar JA, Gaulard P, Ott G, Rosenwald A, Lopez-Guillermo A, gene expression profile but lacking the CCND1 Quintanilla-Martinez L, Harris NL, Jaffe ES, Siebert R, translocation (Fu et al, Blood, 2005). Campo E, Beà S. CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell In 2013, Salaverria et al. investigated 40 well- lymphoma. Blood. 2013 Feb 21;121(8):1394-402 defined CCDN1-negative MCL and identified 22 cases (55%) with CCND2 (cyclin D2) translocations This article should be referenced as such: (Salaverria et al, Blood, 2013). Interestingly, it was Duployez N, Pascal L, Bruge J, Fatoux M, Roche- noted that CCND2 predominantly translocates to IG Lestienne C. The t(2;12)(p12;p13), leading to the light chain genes (15/22, 68%) in contrast with juxtaposition of the cyclin D2 CCND2 gene with the CCND1 translocations. immunoglobulin kappa locus (IGK), defines a small subset of mantle cell lymphomas lacking cyclin D1 Finally, in CCND1-negative MCL, the identification expression.. Atlas Genet Cytogenet Oncol Haematol. of CCND2 gene rearrangement provides a very 2016; 20(3):163-165. robust marker for diagnosis. References

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