Number 7 July 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Volume 1 - Number 1 May - September 1997

Volume 23 - Number 7 July 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.

It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

Jean-Loup Huret, MD, PhD, [email protected]

Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).

Publisher Contact: INIST-CNRS Mailing Address: Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France. Email Address:[email protected] Articles of the ATLAS are free in PDF format, and metadata are available on the web in Dublin Core XML format and freely harvestable.A Digital object identifier (DOI®), recorded at the International Agency CrossRefhttp://www.crossref.org/ is assigned to each article. http://AtlasGeneticsOncology.org

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

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Editor-in-Chief Jean-Loup Huret (Poitiers, France) Lymphomas Section Editor Antonino Carbone (Aviano, Italy) Myeloid Malignancies Section Editor Robert S. Ohgami (Stanford, California) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren and Barnabas Nyesiga (Malmö, Sweden) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France)

Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] 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] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, François Desangles 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Kessel Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Oskar A. Haas Research Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; Roberta Vanni [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 23, Number 7, July 2019 Table of contents

Gene Section

BIRC5 (baculoviral IAP repeat containing 5) 168 Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo SLC45A2 (solute carrier family 45 member 2) 187 Mainak Sengupta, Tithi Dutta, Kunal Ray

Leukaemia Section

Burkitt's lymphoma (BL) 190 Luis Miguel Juárez Salcedo, Ana Corazón Monzón, Samir Dalia t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2 194 Daniel Martinez-Anaya, Rocio Juárez-Velázquez, Dafné Moreno-Lorenzana, Patricia Pérez-Vera

Case Report Section

Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with telomere involvement of 20p in a case of longstanding myelodysplastic syndrome 200 Lubomir Mitev, Liliya Grahlyova, Aselina Asenova, Verginia Uzunova, Julian Raynov A new case of adult Acute Myeloid Leukemia with t(3;3)(p24;q26) 204 Bo Yuan, Janice Smith, April Ewton, Sai Ravi Pingali, Arthur Zieske, Amy Breman t(4;11)(q23;p15) in paediatric early T cell precursor acute lymphoblastic leukemia 207 Anurag Gupta, Sirisharani Siddaiahgari, Nagaraju Nalla, Mukkanteeswara Rao Kasaragadda, Manu Goyal t(6;17)(p21;p13) and acquisition of the Philadelphia chromosome translocation with p190 BCR- ABL1 transcript during the course of myelodysplastic syndrome Adriana Zamecnikova 210 t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML 213 Adriana Zamecnikova Atlas of Genetics and Cytogenetics in Oncology and Haematology

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BIRC5 (baculoviral IAP repeat containing 5) Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, [email protected] (PCB); [email protected] (JAM-N); [email protected] (LVC-L) Brazil; Department of Marine Sciences, Federal University of Sao Paulo, Santos, [email protected] (PCJ), Brazil.

Published in Atlas Database: January 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/BIRC5ID797ch17q25.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70468/01-2019-BIRC5ID797ch17q25.pdf DOI: 10.4267/2042/70468 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA BIRC5, also known as survivin, has been implicated Description in cell cycle progression and apoptosis avoidance. The entire BIRC5 gene is approximately 11.4 Kb BIRC5 is highly expressed in embryonic tissues, (start: 78214186 and end: 78225636 bp; orientation: however very low or absent in adult tissues. BIRC5 Plus strand). overexpression has been frequently associated to cancer development, a poor prognosis and Transcription chemoresistance. Besides that, different BIRC5 There are three transcript variants deposited in the isoforms has been characterized and related to better NCBI database or worse chemotherapy responses depending on the (https://www.ncbi.nlm.nih.gov/gene). isoform and the cancer type. So far, many efforts In general, they present three exons (exon 1, 2 and 3) have been conducted in order to deplete BIRC5 in that are responsible for encoding the BIR domain, cancer cells, including gene therapy, which is conserved in all BIRC family members, and pharmacological and nanotechnological approaches. the exon 4 that is related to the coiled-coil (CC) In this review, we will discuss the role of BIRC5 in domain. cancer cell biology and its clinical significance, Variant 1 is the predominant transcript (cDNA: 2574 demonstrating its DNA/RNA and protein aspects, bp), and encodes isoform 1 (142 amino acids [aa]). also its relevance for diagnosis and prognosis, and Variant 2 lacks an exon in the 3' coding region, advances as a target for the treatment of different which results in a frameshift (cDNA: 2537 bp) and, cancer types. thus, in a changed protein (143 aa) with a different Keywords C-terminus from that of isoform 1 (isoform 2, also BIRC5; Cell cycle progression; Apoptosis; Cancer known survivin-ΔEx3). Variant 3 exhibits an alternate in-frame segment (cDNA: 2724 bp) and Identity generates a longer (165 aa) and distinct protein (isoform 3, also known survivin-2B), compared to Other names: API4, EPR-1 isoform 1. HGNC (Hugo): BIRC5

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 168 BIRC5 (baculoviral IAP repeat containing 5) Branco PC et al.

Figure 1. BIRC5 structure and its splices variants. BIRC5 (also kwon as survivin) presents at least five variants with biological relevance for cancer. A. The protein structure of the most common variant observed presents 142 aa and is composed of a BIR domain that is responsible for its anti-apoptotic activity and a coiled coil. B. The BIRC5 pre mRNA of the most common expressed variant is composed of 3 exons that codifies the BIR domain and the exon 4 that codifies the coiled coil. This variant present anti-apoptotic activity. Survivin Ex3 has its exon 3 deleted and an insertion of a 3'UTR, this isoform codes a protein of 143 aa and also exerts anti-apoptotic functions. Survivin-2B presents an insertion of an exon 2b located between exon 2 and exon 3, generates a protein of 165 aa with pro-apoptotic characteristics. Survivin-2α is characterized by the presence of exon 1 and 2 and the insertion of a 3'UTR, this isoform codifies a protein of 74 aa with pro-apoptotic functions. Survivin-3B presents the insertion of exon 3 b between exon 3 and exon 4, which generates a protein of 165 aa with anti-apoptotic properties. Survivin-3α presents a deletion of exon 3 and generates a protein of 78 aa whose function remain controversial. Arrows indicate the stop codon. UTR- untranslated region. Red line indicates the BIR structure.

Moreover, three additional transcript variants are BIRC6 [bruce], BIRC7 [livin] and BIRC8 [ILP-2]) reported in Ensembl (http://www.ensembl.org/): a there may be between one and three BIR domains, transcript variant containing 568 bp, which generates typically arranged in their N-terminal portion a protein of 74 aa (also known as Survivin-2α); a (Budhidarmo and Day, 2015; Lopez and Meier, transcript variant with 492 bp (cDNA) that produces 2010). a protein of 121 aa (also known as Survivin-3B); and BIRC5 (survivin), the smallest among the IAPs (16.5 a transcript variant comprised of 386 bp (cDNA) that kDa), was discovered in 1997 (Ambrosini et al., gives a protein of 78 aa (also known as Survivin-3α) 1997), is 142 amino acids (aa) long and has a single (Figure 1). BIR domain (Peery et al., 2017). This protein is presented as a stable loop-shaped homodimer, Protein formed by interactions of the N-terminal region through a predominantly hydrophobic interface Description (Chantalat et al., 2000; Verdecia et al., 2000). The IAPs (Inhibitors of Apoptosis Proteins) are a Furthermore, on the C-terminal portion, survivin family of proteins primarily known for inhibiting carries an alpha-helix CC (coiled coil) domain, its caspase activity, either directly or indirectly, thus unique structure (Chantalat et al., 2000; Coumar et preventing apoptotic cell death (Gyrd-Hansen and al., 2013) which convenes the ability to associate to Meier, 2010). Still, the IAPs are further implicated microtubules and a range of other proteins involved, in key roles in other processes, such as cell cycle, cell mainly, in the process of mitosis, and further migration, inflammation and, even, in the innate allowing for translocation among the different immune response (de Almagro and Vucic, 2012). cellular compartments, such as mitochondria, Structurally, members of the IAPs are characterized cytoplasm and nucleus (Rodel et al., 2012) (Figure by the presence of at least one BIR (Baculovirus IAP 1). repeat) domain, which contains nearly 80 amino acid Since BIRC5 is connected to a diverse network of residues and carries Zn2+ in the center. Such domain biochemical processes and therefore has remarkable is a highly conserved sequence that mediates multifunctionality, its modulation in cancer therapy protein-protein interactions, an essential feature for continues to be extensively explored. Several their anti-apoptotic function. Within the eight human survivin inhibitors have been identified by in vitro IAPs recognized ( NAIP [BIRC1], BIRC2 [cIAP1], and in silico methods, such as antisense BIRC3 [cIAP2], XIAP [BIRC4], survivin [BIRC5], oligonucleotides, siRNA, dominant-negative

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mutants, peptidomimetic molecules and other small those vesicles promoted increased cell sensitivity to inhibitory molecules, and even as anticancer vaccine chemotherapeutic agents (Kreger et al., 2016). (Fenstermaker et al., 2016; Sarvagalla et al., 2016). Function Expression Studies have shown that overexpression of BIRC5 BIRC5 is normally expressed in embryonic tissues inhibits both the intrinsic and extrinsic pathways of and during fetal development, as well as in fast apoptosis and the depletion of survivin in human cell dividing normal cells (like bone marrow stem cells, culture impairs apoptosis and triggers cell division basal epithelial cells and thymocytes, even if at lower defects (Li et al., 1998; Roy et al., 2015). The concentrations), but is virtually undetectable in fully antiapoptotic mechanism of BIRC5 still needs to be differentiated and healthy adult tissues (Adida et al., better clarified, however, both the direct or indirect 1998; Sah et al., 2006; Stauber et al., 2007). binding of BIRC5 to caspases are proposed (Figure Throughout the cell cycle, BIRC5 is expressed only 2) (Altieri, 2013; Garg et al., 2016; Li et al., 1998). during mitosis, in a highly regulated manner Evidences also indicate that BIRC5 binds to XIAP, comprising the chromosomal passenger complex one of the best studied IAPs, forming a complex that (CPC), as it interacts with tubulin and kinetochores protects XIAP against ubiquitination and during metaphase, then participates in central proteosomal degradation. spindle organization and cytokinesis, throughout This complex then activates multiple signaling anaphase (Szafer-Glusman et al., 2011). pathways, including NF-κB, inhibits caspases However, BIRC5 is expressed in cells that undergo CASP3, CASP7 and CASP9, suppresses apoptosis malignant transformation, being overexpressed in and accelerates tumor progression. Other numerous tumors (Altieri, 2001; LaCasse et al., cytoprotective mechanisms have been proposed for 2008). Recent studies evidenced that transcriptional BIRC5, including the ability of mitochondrial activation is not the only cause for BIRC5 BIRC5 to sequester the pro-apoptotic DIABLO overexpression, but also post-transcriptional (Smac) protein from its binding to BIRC4 (also regulation, specially coordinated by many known as XIAP), or even preventing its release from alternative polyadenylation (APA) sites. For mitochondria (Altieri, 2013; Coumar et al., 2013; instance, in ovarian cancer, aberrant APA leads to Song et al., 2003). shortening of the 3'-UTR region, enabling escape Interaction of BIRC5 with CDK4 has been from negative regulation of miRNAs and causing associated with progression of the cell cycle. In up-regulation of BIRC5 (He et al., 2016). mitosis, BIRC5 plays a key role in integrating the Clinically, overexpression of BIRC5 has been transient chromosome complex (CPC), along with correlated with a poor prognosis of cancer, resistance INCENP, CDCA8 (borealin) and AURKB, which to apoptosis induced by chemotherapy, decreased controls the formation and stabilization of the survival of patients and greater chances of relapse mitotic spindle (Altieri, 2013; Coumar et al., 2013). (Islam et al., 2000; Rodel et al., 2012). Activation of Wnt signaling induces β-catenin ( CTNNB1) and BIRC5 nuclear translocation, which Localisation contributes in mitotic spindle formation, further BIRC5 is located both in the cytoplasm and in the regulating CPC, β-catenin, STAT3 and HIF1A nucleus. Nuclear expression has been associated (Figure 2). BIRC5 also appears to be involved in the with a poor prognosis and chemoresistance (Du et cellular response to stress through the interaction al., 2015), which may differ among the different with various chaperones, such as AIP, HSPD1 types of cancers (Shintani et al., 2013). BIRC5 splice (HSP60) and HSP90AA1 (HSP90) (Altieri, 2013; variants were also related to subcellular localization. Fortugno et al., 2003). Moreover, BIRC5 also This has been shown in samples from acute myeloid partakes in the process of autophagy (Wang et al., leukemia patients, where wild-type survivin and the 2011) and in DNA repair among several tumor cell 2B splice variant were expressed in the nucleus, lines (Jiang et al., 2009). cytoplasm or both, whereas the ΔEx3 isoform was BIRC5 has also been shown to induce cell motility, only expressed in the nucleus (Serrano-Lopez et al., metastasis and increased colonization capacity by 2013). However, considering pro-survival factors, AKT-mediated upregulation of the α5 integrin localization is not the only relevant feature: it has pathway in a melanoma model (McKenzie et al., been recently demonstrated that BIRC5 can be 2013). packaged into extracellular vesicles (endosomes) Additionally, BIRC5 plays an important role in and its delivery may be guided by antiapoptosis angiogenesis, contributing to endothelial cell stimuli from cancer cells and tumor proliferation and migration, which was then linked microenvironment, inducing pro-survival to increased β-catenin protein levels that competences in fibroblasts after treatment with consequently promotes an elevated expression of paclitaxel. Conversely, knockdown of BIRC5 in BIRC5 and VEGF (Fernandez et al., 2014).

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Figure 2. BIRC5: a multitask protein. BIRC5 (survivin) acts on cytoplasm and nucleus and is involved different cellular functions: cell survival, cell cycle progression, mitotic spindle formation and transcription activation. In cytoplasm, BIRC5 modulates apoptosis pathway by binding to and blocking initiator caspase 9 and effectors caspases 3 and 7, demonstrating to be involved in extrinsic and intrinsic apoptosis and contributing to cell survival. BIRC5 may be blocked by SMAC/DIABLO, a factor released by mitochondria. Also BIRC5 potentiates apoptosis inhibition through stabilization of BIRC4 (also kwon as XIAP). TGF-β signaling negatively regulates BIRC 5 by phosphorylating SMAD protein. p53-mediated signaling also downregulates BIRC5 functions. CDC phosphorylates BIRC5 and promotes its binding to CDK4 that may be translocated to nucleus, and thus promotes cell cycle progression. In nucleus, BIRC5 is involved in the mitotic spindle formation modulated by Wnt pathway through the phosphorylation inhibiton and nuclear translocation of β-catenin activating BIRC5 and associated to other proteins (not shown) form the Chromosomal Passenger Complex (CPC). The transcription activation of BIRC5 mRNA is mainly promoted by β- catenin, STAT3 (signal transducer and activator of transcription-3) and HIF 1 α (hypoxia-inducible factor-1α).

BIRC5 is also directly involved in enhancing anoikis autophagy followed by cell death induced by resistance through miR-141/KLF12/Sp1/survivin accumulation and stabilization of IKBKB (IKKB) in axis. It is a consensus that anoikis resistance is the nucleus (Shi et al., 2014). crucial for establishing a metastatic niche and Homology consequently promoting cancer progression and dissemination (Mak et al., 2017). Dissimilar The BIRC5 gene is highly homologous among functions have been attributed to the different different species, as shown in Table 1, which isoforms of BIRC5. Survivin-2α and survivin-2B demonstrates the comparison of variant 1 among portray a proapoptotic activity profile, whereas different species. Survivin-ΔEx3 and Survivin-3B show prominent % Identity for: Homo Symbol Protein DNA antiapoptotic activity, with similar activities to those sapiens BIRC5 of survivin itself. These distinct variants can predict vs. P. troglodytes BIRC5 98.3 98.8 aggressiveness of cancer phenotype, thus contributing to prognosis (Caldas et al., 2005). vs. M. mulatta BIRC5 97.9 97.9 BIRC5 can be released from tumor cells in exosomes vs. C. lupus BIRC5 90.8 90.1 (Khan et al., 2011). This information provided new insights into biomarkers for determination of early vs. B. taurus BIRC5 90.1 90.1 diagnosis and also to predict prognosis. In this vs. M. musculus Birc5 83.6 82.6 context, the splice variant survivin-2B, in breast vs. R. norvegicus Birc5 83.0 81.3 cancer, was shown to be expressed mostly in primary tumors and exclusively in early stage disease. vs. G. gallus BIRC5 60.6 65.7 Conversely, Survivin-ΔEx3 variant was most vs. X. tropicalis birc5.2 57.8 64.2 commonly expressed in late stages of breast cancer (Khan et al., 2014). Survivin-2B has been further vs. D. rerio Birc5a 54.3 58.0 reported to promote cell death in some cancer cells Table 1. Comparative identity of human BIRC5 with other by promoting species (Source: http://www.ncbi.nlm.nih.gov/homologene)

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YM155 treatment reduced BIRC5 expression, and Mutations induced apoptosis and DNA fragmentation (Lai et Somatic al., 2012). Similar results were reported by Jane and colleagues (Jane et al., 2013), where YM155 Recurrent mutations in the BIRC5 gene are rare. downregulated BIRC5 and MCL1 expression and Among the 47,119 unique samples reported in inhibited cell growth in malignant human glioma COSMIC (Catalogue of Somatic Mutations in cells. Interestingly, in resistant glioma cell lines Cancer; attributed to EGFR activation, YM155 alone did not http://cancer.sanger.ac.uk/cancergenome/projects/c present any significant effects, however in osmic), only 43 presented BIRC5 mutations (29 combination with ABT-373, a BH3-only mimetic missense substitutions, 8 synonymous substitutions, that targets the prosurvival members of the BCL2 3 nonsense substitutions and 2 frameshift insertions). family, a synergic effect mediated by caspase Similar findings are reported in cBioPortal activation was observed (Jane et al., 2013). (http://www.cbioportal.org) among the 55,481 Depletion of BIRC5 levels mediated by parthenolide cancer samples accessed, that show somatic treatment induced apoptosis and cell cycle arrest in mutations in BIRC5 occur in merely 0.2% of the glioblastoma cell lines (Tang et al., 2015). tested samples (corresponding to 116 mutations, of Cucurbitacin-I, another natural product, induced cell which 65 are missense substitutions, 50 truncated death in malignant glioma cells, while promoting genes or 1 other mutation). When mutations, G2/M accumulation, depletion of p-STAT3, p- amplifications, deep deletions and multiple STAT5, p-JAK1 and p- JAK2 levels, and alterations were considered, the total of cancer downregulation of AURKA, AURKB and BIRC5 samples with any type of genetic alteration in BIRC5 (Premkumar et al., 2015). Medulloblastoma also was 969 (1.7%). presents elevated level of BIRC5 expression, as observed for other brain cancers. Similarly, Implicated in antagonists of BIRC5 impaired proliferation and Angiosarcoma survival of both murine and human medulloblastoma cells (Brun et al., 2015). High BIRC5 expression was In a cohort including 85 samples from angiosarcoma associated to advanced stages and sporadic tumors in patients and 88 controls (54 hemangioma and 34 patients aged greater than 12 months (Islam et al., pyogenic granuloma), nuclear BIRC5 expression 2000), which negatively impacted clinical outcomes was observed in all angiosarcoma patients, but in (Azuhata et al., 2001). In addition, BIRC5/p53 and fewer than 7% of the control group. This data BIRC5/FAS ratios have been implicated in indicates that BIRC5 expression may be used as a neuroblastoma prognosis (Sandler et al., 2002; Tajiri diagnosis tool in angiosarcoma (Tsuneki et al., et al., 2001). In neuroblastoma and 2017). In addition, genetic or pharmacological oligodendroglioma cell lines, BIRC5 silencing BIRC5 inhibition reduces cell proliferation in ISO- reduced cell viability while further inducing mitotic HAS-B human angiosarcoma cells (Tsuneki et al., catastrophe and cell death by caspase-dependent and 2017). -independent pathways (Shankar et al., 2001). Brain cancer Breast cancer Western blot analysis revealed that BIRC5 was BIRC5 protein expression was found in 78% of high- expressed in 60.3% of glioma samples, which was grade and 21.4% of low-grade patients with ductal associated with a reduced apoptosis ratio and high- carcinoma in situ, indicating that BIRC5 expression grade tumors (Bae et al., 2017). In agreement, is associated with an advanced stage phenotype in samples obtained from gliosarcoma patients breast cancer (Chade et al., 2018). In addition, presented elevated expression of BIRC5 in the increased nucleus of tumor cells collected from brain lesions, Estrogen positive breast cancer subtypes have been when compared to normal brain cells (Chen et al., connected to increased BIRC5 regulation, w levels 2010). of BIRC5 mRNA (2.24 fold) were observed in whole BIRC5 expression was also associated to blood samples from breast cancer patients when radioresistance: ionization of glioblastoma cell lines compared to healthy donors (Wang et al., 2016). promoted BIRC5 upregulation, which mediated Estrogen positive breast cancer subtypes have been dedifferentiation to a stem-like phenotype and, connected to increased BIRC5 regulation, which was consequently, induced a radioresistant phenotype reverted by treatment with the natural compound (Dahan et al., 2014). myricetin, enhancing apoptosis (Jiao and Zhang, Treatment of glioma cells with the survivin inhibitor 2016). In triple negative breast cancer, YM155 overcomes resistance to TRAIL-induced chemoresistance and metastasis were associated to apoptosis, by downregulating MCL1 and BIRC5 elevated DEPTOR protein expression that, in turn, (Premkumar et al., 2013). In glioblastoma cell lines, induced a higher expression of BIRC5, both in vitro

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and in vivo (Parvani et al., 2015). Survivin and In breast cancer cell lines, including triple negative survivin-ΔEx3 were overexpressed and associated to phenotype and tamoxifen-resistant cells, YM155, a chemoresistance in non-responder samples using ex BIRC5 inhibitor, as previously mentioned, reduces vivo organotypic cultures of primary human breast cell viability, with IC50 values in the low nanomolar tumors (Faversani et al., 2014). Using shRNA range, and induced autophagy (Cheng et al., 2015). targeting BIRC5 splice variants isoforms, Zheng and In breast cancer cell lines, ABT-263 (navitoclax), a colleagues (Zheng et al., 2011) demonstrated that BCL2 family protein inhibitor, promoted a negative apoptosis rates were improved considerably by modulation of BIRC5 levels in MDA-MB-231, but survivin depletion, but survivin-ϚEx3 isoform not in MCF-7, which was associated with a higher silencing only moderately inhibited cell survival and sensitivity to the drug (Lee et al., 2018). growth in a breast cancer model. In breast cancer cells, combined therapy using Cervical carcinoma panobinostat with gemcitabine markedly diminished In a recent meta-analysis including eleven studies BIRC5 expression (Budman et al., 2012). Similarly, and a total of 865 cervical carcinoma patients, Cheng SMAC mimetics (BV6, Birinapant) and BH3- and colleagues (Cheng et al., 2016) reported that mimetics (ABT-737/263) combined with paclitaxel elevated BIRC5 expression was positively treatment demonstrated positive results regarding associated with aggressive clinicopathological BIRC5 downregulation (Panayotopoulou et al., features, lymph node metastasis and poor survival 2017). outcomes. Chemoresistance was also related to the extracellular LGALS1 (galectin-1) expression that, moreover, Colorectal cancer contributes to cancer progression and doxorubicin Immunohistochemical analysis evidenced that resistance in triple negative breast cancer. It must be patients with colorectal adenocarcinomas exhibited stated, herein, that galectin-1 expression is mediated higher BIRC5 levels compared to adjacent non- by STAT3 activation, which is a transcription factor tumor colorectal mucosa. In the same study, the that culminates in BIRC5 upregulation, authors demonstrated that BIRC5 silencing, by corroborating the role of BIRC5 in chemoresistance siRNA, suppressed survival and cell invasion, and in breast cancer cells (Nam et al., 2017). The induced cell cycle G0/G1 arrest and apoptosis in function for STAT3 in BIRC5 upregulation in breast colorectal cancer cells (Wang et al., 2017b). BIRC5 cancer cells was also confirmed by Wang and splice variants were also evaluated in colorectal colleagues (Wang et al., 2015), who demonstrated cancer, and the distribution of mRNA observed was that MIR204 inhibits STAT3 activation and BIRC5 the following: 48% of wild-type survivin, 38% of expression. survivin-2B isoform and 29% of survivin-ΔEx3 BIRC5 also participates on the invasive phenotype isoform. The mRNA expression of wild-survivin and by regulating the expression of the vascular survivin-ΔEx3 was related with tumor size and endothelial growth factor-C ( VEGFC) at both invasion, respectively (Pavlidou et al., 2011). In protein and mRNA levels, which culminates in a contrast, BIRC5 levels were not associated with raised metastasis rate in breast cancer (Cai et al., patients with advanced colorectal adenoma (Choi et 2012). In agreement, elevated BIRC5 expression al., 2017). was associated with poor prognostic in stage II/III Elevated expression of BIRC5 was also correlated breast cancer patients (Hamy et al., 2016). The with levels of CD133+, which is associated to authors proposed that BIRC5 expression might be chemoresistance to 5-fluorouracil, in colon cancer theranostic, and suggest that high BIRC5-expressing cells. The elevated expression of BIRC5 induced by breast cancer patients would be randomized to activation of the CXCL12/ CXCR4 signaling receive BIRC5 targeting drugs (Hamy et al., 2016). pathway in cells exposed to radiation may be a A recent study that evaluate the transcriptome of crucial factor for the acquisition of chemoresistance primary breast cancer patients, demonstrated that, in this cancer type (Wang et al., 2017a). However, along with NEK2 and TOP2A, BIRC5 gene was no association was found between expression of amplified in obese breast cancer patients, reinforcing BIRC5 and invasion, lymph node metastasis, nor that this gene may be druggable for this population histologic differentiation (Li et al., 2017). Survivin (Nuncia-Cantarero et al., 2018). One factor that may depletion by the EpCAM-aptamer-guided BIRC5 explain such observation is the synthesis of visfatin, RNAi enhanced colorectal cancer stem cells an adipokine secreted by adipocytes, macrophages sensitivity to 5-FU and oxaliplatin, further inducing and inflamed endothelial tissue, which was found to apoptosis, reducing tumor growth and improving the be increased in obese and breast cancer patients, overall survival in a colorectal cancer xenograft while exerting a protective effect on BIRC5, raising model (AlShamaileh et al., 2017). its levels and, thus, contributing to tumor The use of natural products was also implicated in progression (Gholinejad et al., 2017). reduction of BIRC5 levels, such as tanshinone I, an active compound from traditional Chinese herbal

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medicine (Lu et al., 2016), and the Pinus roxburghii Head and neck squamous cell essential oil (Sajid et al., 2018). Additionally, carcinoma treatment with tamoxifen β-estradiol or a combination of these two agents promoted decreased Hih levels of BIRC5 was observed in samples from BIRC5 levels and impaired cell migration in head and neck squamous cell carcinoma patients, colorectal cancer cells (Ou et al., 2017). In colon which was associated with poor survival outcomes cancer cells, dimethoxy curcumin inhibited cell and chemotherapy resistance (Zhang et al., 2015a) In growth, increased apoptosis, reduced cell migration, head and neck squamous cell carcinoma cells, a downregulated BIRC5 expression and enhanced treatment targeting BIRC5 by using YM155 CDH1 (E-cadherin) in vitro and in vivo (Chen et al., increased apoptotic and autophagic cell deaths, 2016). suppressing pro-survival pathways (Zhang et al., Treatment failure in colorectal cancer was 2015a). previously associated to the presence of stem cells Similarly, treatment with an aliphatic hydroxamate- bearing a KRAS mutation, which, then, become based compound targeting BIRC5 reduced survivin resistant to chemotherapy. Treatment with Omega-3 levels through LKB1/AMPK/p38MAPK signaling, fatty acid DHA promoted a reduction of cell and further enhanced p63 phosphorylation and p21 viability, with caspase-3 activation mediated by a activation (Yen et al., 2018). decrease in transcript and protein levels of BIRC5 Hepatocellular carcinoma and, moreover, an increase in MIR16-1 expression In SMMC-7721 hepatocellular carcinoma cells, levels, suggesting that BIRC5 and microRNA-16-1 treatment with berbamine, a natural compound from to be promising molecular targets of DHA (Sam et Chinese medicine, promoted upregulation of p53 al., 2018). expression and downregulation of BIRC5, which Endometrial cancer further triggered mitochondria signaling pathway- In endometrial cancer, BIRC5 was identified to be mediated apoptosis (Cao et al., 2018). critical for NEF2-driven progestin resistance. The Kidney cancer authors also demonstrated that BIRC5 silencing In renal cell carcinoma patients, high BIRC5 enabled restoration of progestin sensitivity in NRF2- expression was associated with increased TNM stage overexpressing RL-95-2 cells (Fan et al., 2017). and high Fuhrman grade, which indicates that Gastric cancer BIRC5 may be a good prognosis predictor (Ma et al., Gastric adenocarcinoma patients undergoing 2017). gastrectomy were evaluated for the expression of Furthermore, BIRC5 has been associated with tumor markers with relevance for tumor progression and progression and chemoresistance to temsirolimus, an prognosis. Among them, 93.9 % of samples from MTOR inhibitor. Strategies that abrogate survivin gastric cancer patients presented nuclear sub- expression, such as shRNA-mediated BIRC5 localization of BIRC5, which was associated with a silencing or pharmacological approach (YM155), poor prognosis (Lins et al., 2016). It has been reduced chemoresistance of renal cell carcinoma demonstrated that BIRC5 upregulation increased cells in vitro and in vivo (Carew et al., 2015). VEGF expression in gastric cancer (Zhang et al., Other signaling pathways seem to converge to the 2014). The authors also demonstrated that 51.3% of induction of BIRC5 expression in renal cell gastric carcinoma samples presented BIRC5 carcinoma. expression, which was located mainly in the For instance, combined treatment between the cytoplasm of tumor cells, associated with lymph histone deacetylase (HDAC) inhibitor OBP-801 and node metastasis and reduction of overall survival in the phosphatidylinositol 3-kinase (PI3K) inhibitor the univariate analysis (Zhang et al., 2014). LY294002 synergistically inhibited cell growth and BIRC5 knockdown using shRNA promoted an induced apoptosis in renal cell carcinoma through elevated sensitivity to radiation and chemotherapy BIRC5 downregulation (Yamada et al., 2013). using 5-FU, demonstrating that the modulation of Leukemia BIRC5 levels may be an important adjuvant therapy for gastric cancer patients (Shen et al., 2012). In In chronic myeloid leukemia, the oncogenic agreement, BIRC5 silencing mediated by siRNA signaling induced byBCR/ ABL1 leads to BIRC5 increased apoptosis rates, inhibited cell proliferation upregulation by activating the JAK2/STAT3 in a cisplatin-resistant cell line (Li et al., 2014) and pathway. impaired cell migration in gastric cancer cells (Li et al., 2015). Moreover, BIRC5 silencing promoted pronounced cytotoxic effect in both imatinib-sensitive and - resistant chronic myeloid leukemia cell lines, a similar effect to that observed after treatment with

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shepherdin, a cell-permeable peptidomimetic development in a cohort including 182 childhood compound that downregulates BIRC5. These acute leukemia patients and 200 controls. findings indicate that survivin may be a target in BIRC5-overexpressing leukemias (Stella et al., Liver cancer 2013). The combined use of C82 (a Wnt/β-catenin In samples from hepatocarcinoma patients, 55.4% of signaling modulator) and nilotinib in chronic tumor tissues were positive for BIRC5 expression, myeloid leukemia progenitor cells inhibited the which was higher when compared to non-tumor expression of CD44, MYC, BIRC5, p-CRKL and p- adjacent tissues (2%). Additionally, BIRC5 STAT5 (Zhou et al., 2017) expression has been directly correlated with In acute myeloid leukemia, BIRC5 overexpression is unfavorable clinical staging and tumor score, and the involved in drug resistance of leukemia stem cells, presence of extrahepatic metastasis. The authors also regulated by the ERK/MSK/Sp1/MYC axis (Zhang demonstrated a positive correlation between BIRC5 et al., 2015b). Interestingly, BIRC5 depletion, by and VEGF expression, implying that besides siRNA, reduced cell proliferation, induced avoiding apoptosis, BIRC5 may induces apoptosis, and synergistically enhanced cytotoxicity angiogenesis contribute to tumor dissemination of etoposide in acute myeloid leukemia cells (Tian et al., 2018). (Karami et al., 2013). Other molecular signaling that has been involved in acute myeloid leukemia Lung cancer resistance is the expression of MUC1 (MUC1-C), an A meta-analysis study including 3,206 non-small oncoprotein critical for the onset of tumorigenesis, cells lung cancer (NSCLC) patients and 816 normal which is overexpressed in acute myeloid leukemia controls, BIRC5 was found to be overexpressed in blasts and leukemia stem cells. It has been tumor samples and strongly correlated with demonstrated that targeting MUC1-C reduced histological differentiation, tumor-node-metastasis BIRC5 levels and increased sensitivity to cytarabine, stage and lymph node metastasis, which indicates indicating that BIRC5 is involved in multiple that BIRC5 may be a tumor progression marker for signaling pathways required for survival in leukemia such cancer type (Duan et al., 2016). Another study cells (Stroopinsky et al., 2018). indicated that BIRC5 may be involved in Acute lymphoblastic leukemia (ALL) patients also chemoresistance of NSCLC cells (Hu et al., 2016). presented elevated levels of BIRC5 and VEGF, Additionally, it was demonstrated that the GC+CC especially prior to treatment with an association of genotypes in the promoter region (-31) of the BIRC5 idarubicin, cytosine arabinoside and etoposide. gene (polymorphism rs9904341) were significantly Nevertheless, those levels decreased after treatment associated with EGFR mutations in a cohort of 360 (Yang et al., 2013). In children diagnosed with acute lung cancer patients (Liu et al., 2016). lymphoblastic leukemia, BIRC5 expression was Recently, BIRC5 was identified as a target of higher compared to healthy donors. The same group MIR195, a microRNA that induced apoptosis and of patients was monitored during the entire treatment senescence in NSCLC cells (Yu et al., 2018). A period and those who went in to complete remission combined therapy using the natural product of the disease presented decreased levels of BIRC5, resveratrol and the epidermal growth factor receptor compared to diagnosis sample. In contrast, BIRC5 (EGFR) inhibitor erlotinib promoted an increase in protein levels were elevated in non-survived ALL cell death mediated by BIRC5 depletion in NSCLC patients (Yahya et al., 2012). In acute lymphoblastic cells (Nie et al., 2015). Similarly, depletion of leukemia primary samples and cell lines, treatment BIRC5 induced by treatment with YM155 increased with YM155 exhibited elevated cytotoxicity by the sensitivity of such cells to radiation (Hu et al., induction of DNA damage, leading to 2015). phosphorylation of CHEK2 and H2AFX and Treatment with the natural product fisetin also promoting suppression of BIRC5 expression (Chang increased sensitivity to cisplatin in cisplatin-resistant et al., 2015). NSCLC cells by modulation of It is well accepted that leukemia stem cells MAPK/BIRC5/Caspase axis (Zhuo et al., 2015). contribute to a reduced treatment efficacy and also to Lung cancer stem cells were more sensitive to chemoresistance. The natural product curcumin FL118, a BIRC5 inhibitor, than cisplatin. decreased BIRC5 levels in leukemia stem cell-like Additionally, FL118 downregulated cancer stem cell KG1a in a combined treatment with busulfan, which related markers, which may improve drug-sensitivity may overcome such chemoresistant of leukemia in this kind of tumor cells (Wang et al., 2017c). stem cells (Weng et al., 2015). Lymphoma Furthermore, Li and colleagues (Li et al., 2018) observed an association between the presence of C In non-Hodgkin lymphoma, specifically the allele of BIRC5 polymorphism rs9904341, but not of aggressive subtype extranodal natural killer/T-cell rs8073069, and an increased risk of acute leukemia lymphoma, which is frequently associated with resistance to anthracyclines, presence of BIRC5

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serum levels were detected in approximately 25% of and increased tendency for lymph node and lung patients, which is associated with advanced stages of metastasis (Thomas et al., 2007). Furthermore, the disease. In addition, the percentage of lymphoma BIRC5 overexpression in melanocytes activated the cells that demonstrated BIRC5 nuclear localization AKT and MAPK signaling pathways, acquiring a was significantly associated with BIRC5 serum more invasive phenotype, and demonstrating the concentration (Kim et al., 2015). involvement of BIRC5 on the onset and progression BIRC5 expression was positive in 40% of lymph of melanoma (McKenzie et al., 2013). node biopsy of diffuse large B-cell lymphoma In melanoma cells, BIRC5 was associated to patients. Such observation correlated with enhanced AKT and MAPK signaling dependent unfavorable factors for therapy response and migration and invasion, as well as to the predicted shorter survival outcomes (Markovic et al., upregulation of ITGA5 (α5 integrin) (McKenzie et 2012). A meta-analysis, including 17 studies and al., 2010). BIRC5 silencing through RNA 1,352 diffuse large B-cell lymphoma patients, found interference promoted cell cycle arrest and reduced positive BIRC5 expression to be associated with cell proliferation and metastasis in vivo and in vitro advanced clinical stages and reduced overall survival in melanoma models. Moreover, as observed for (Zhang et al., 2015c). other tumor types, BIRC5 inhibition led to increased The combinatory use of bendamustine and rituximab sensitivity to chemotherapy in melanoma cells associated with BIRC5 inhibitor, YM155, presented (Kedinger et al., 2013). In another study, a proposed potentiating effects on induction of cell death by strategy to overcome chemoresistance and to triggering DNA damage and cell cycle arrest in promote melanoma cell death was the combination lymphoma cells, and, moreover, reduced tumor size of vemurafenib and Nutlin-3, whose synergism was and metastatic capacity in diffuse large B-cell responsible for BIRC5 depletion and apoptosis lymphoma xenograft murine models (Kaneko et al., induction (Ji et al., 2013). 2014). A combined treatment of rituximab and Pharmacological suppression of BIRC5 expression, YM155 was shown to reduce tumor growth more using YM155, increased apoptosis induction and effectively than monotherapy (Kita et al., 2012). In tumor regression in melanoma xenograft models. In B and T cell lymphoma cells, BIRC5 abrogation the same study, combined treatment of YM155 and using the non-toxic tellurium compound, AS101, has docetaxel presented potentiating effects in induction overcome chemoresistance, sensitizing these cells to of apoptosis compared to monotherapy, paclitaxel (Danoch et al., 2015). BIRC5 expression corroborating the notion that targeting BIRC5 may presented anti-apoptotic functions and is regulated be an interesting approach in melanoma by NF-κB and PI3K/AKT signaling pathways in management (Yamanaka et al., 2011). Similar nasal NK/T-cell lymphoma cells (Sun et al., 2015). results were obtained using natural compounds Malignant pleural mesothelioma extracted from plants that target BIRC5 through β- catenin and STAT3 suppression (Habibie et al., In two independent cohorts of malignant pleural 2014). mesothelioma patients, nuclear BIRC5 expression in Another alternative approach for targeting BIRC5 both, pre- and post-chemotherapy tissues, was was the generation of recombinant fusion proteins associated with shorter freedom from recurrence and containing the TAT protein transduction domain and overall survival, indicating that BIRC5 expression either wild-type survivin (TAT-Surv-WT) or a may be a prognostic factor for poor clinical dominant- negative mutant (TAT-Surv-T34A). The outcomes in this cancer type (Meerang et al., 2016). mutant promoted in vitro cell death through Melanoma apoptosis and DNA fragmentation in melanoma cells. In vivo injections of such mutant in melanoma BIRC5 expression was previously demonstrated in xenograft mice increased apoptosis, induced melanoma and melanocytic nevus, which aberrant nuclei formation and impaired tumor demonstrated all nevi, regardless of histologic type, growth (Yan et al., 2006). expressed detectable levels of BIRC5 (Yan et al., BIRC5 mRNA was detected in 98% of samples from 2006). Additionally, a cytoplasmic staining of metastatic melanoma patients. High BIRC5 mRNA BIRC5 was evidenced in dysplastic nevi (Florell et levels were significantly associated with poor overall al., 2005). In normal melanocytes, it was survival (Takeuchi et al., 2005). demonstrated that p53 and RB1 are required to repress BIRC5 expression. A role for E2F2 in the Multiple myeloma negative regulation of BIRC5 expression was also BIRC5 expression was positive in 35% of samples pointed out (Raj et al., 2008). Increased BIRC5 from newly diagnosed multiple myeloma patients, expression was observed in vivo in melanocytes that but no association with clinical and laboratorial were more resistant to UV-induced apoptosis, which characteristics, treatment response and survival was further associated to lower rates of spontaneous outcomes was found (Zeng et al., 2014). On the other apoptosis, earlier melanocytic tumor development hand, Yang and colleagues (Yang et al., 2016b), in a

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study that evaluated the efficacy of a combination expressed higher BIRC5 mRNA levels than their treatment with fludarabine, vincristine, epirubicin, taxane-sensitive counterparts. Survivin-2B dexamethasone and thalidomide (FVADT) expression was significantly higher in taxane- chemotherapy regimen for refractory multiple resistant cells, when compared to sensitive cells myeloma patients, reported that complete remission (Vivas-Mejia et al., 2011). and efficacy rates were significantly lower in the YM155 treatment induced BIRC5 downregulation, BIRC5-positive group, when compared with the cell growth inhibition, cell cycle arrest, reactive BIRC5-negative group. oxygen species formation and apoptosis, and Myxoid liposarcoma enhanced docetaxel efficacy in ovarian cancer cell lines (Hou et al., 2018). In agreement, in ovarian Using high-throughput drug screen and myxoid cancer cells, BIRC5 knockdown enhanced cisplatin liposarcoma cell lines, BIRC5 has been identified as sensitivity in resistant cancer cells, inducing a relevant protein important for cell survival (de apoptosis and inhibiting the invasive process through Graaff et al., 2017). downregulation of MMP2 (Jiang et al., 2013). Oral squamous cell carcinoma Pancreatic cancer Elevated BIRC5 mRNA expression was observed in In a cohort of 51 pancreatic adenocarcinoma samples from oral squamous cell carcinoma patients patients, BIRC5 expression was found in 49% of compared to peritumoral or normal tissues (Li et al., samples and was associated with poor survival 2012). Still, such increase was shown to be outcomes (Contis et al., 2018). Similar results were insufficient to drive tumor progression in oral reported by Zhou and colleagues (Zhou et al., 2018), squamous cell carcinoma, however nuclear who described that nuclear BIRC5 was higher in expression of BIRC5 was correlated with tumor tumor compared to non-tumor pancreatic tissues, stage and differentiation grade (Liu et al., 2017). and a high nuclear BIRC5 expression was an Additionally, the authors suggested that nuclear independent predictor of disease-specific survival in localization of BIRC5 has been due to the acetylation ductal pancreatic adenocarcinoma patients. In at K129 in the protein C-terminal region (Liu et al., pancreatic cancer models, FL118, a BIRC5 inhibitor, 2017). In oral squamous cell carcinoma cells, reduced cell viability, including for stem cell like and treatment with YM155 reduced BIRC5 levels and cisplatin-resistant cells, and decreased xenograft increased apoptosis rates (Yan and Su, 2017). tumor growth and metastasis (Ling et al., 2018). Ovarian cancer Prostate cancer High BIRC5 levels correlate with advanced stage, BIRC5 levels was not detected in normal tissues, metastasis and poor disease-free survival in ovarian slightly detected in benign prostate hyperplasia cancer (Aune et al., 2011; No et al., 2011). tissues and considerably higher in prostate Moreover, BIRC5 serum levels were significantly adenocarcinoma, which was positively correlated higher, while DIABLO (Smac) levels were with higher tumor stage (Eslami et al., 2016). In significantly lower in patients with serous ovarian agreement, increased BIRC5 levels were also carcinoma when compared to healthy controls associated with poor survival outcomes in prostate (Dobrzycka et al., 2015). cancer patients (Xu et al., 2015). The association of nuclear and cytoplasmic BIRC5 In a cohort including 157 prostate cancer patients expression and prognosis remains controversial in and 145 controls, genetic polymorphisms c.-31G>C ovarian cancer. The evaluation of BIRC5 expression (rs9904341), c.454G>A (rs2071214), and c. in patients treated with taxane and platinum agents *148T>C (rs1042489) of BIRC5 were associated concluded that, in this treatment regimen, higher with risk for prostate cancer development (Karimian nuclear BIRC5 expression was associated with et al., 2018). reduced risk of disease recurrence and death Treatment with BIRC5 inhibitor (YM155) inhibited (Felisiak-Golabek et al., 2011). By contrast, another cell growth, cell migration and invasion in prostate study reported that nuclear BIRC5 was significantly cancer cells (Xu et al., 2015). Overexpression of associated with chemoresistance to taxane-based miR-494 (a microRNA targeting BIRC5) and/or chemotherapy, predicting poor progression-free BIRC5 silencing using shRNA attenuated cell survival (Du et al., 2015). Immunohistochemistry growth in vitro and in vivo (Zhu et al., 2016). analysis revealed that BIRC5 expression presented a Moreover, treatment of prostate cancer cells with a positive correlation with FIGO stage in epithelial selective inhibitor of nuclear export, KPT-330, ovarian cancer, benign epithelial ovarian tumor inhibited proliferation and promoted apoptosis of tissue and borderline ovarian tumor tissues (Ju et al., tumor cells, by increasing protein degradation of 2016). exportin XPO1, BIRC5 and CCND1, further leading BIRC5 splices variants were also correlated to the to cell cycle arrest and apoptosis (Gravina et al., development of ovarian cancer and resistance to 2015). Natural products, such as the triterpenoid chemotherapy. Taxane-resistant ovarian cancer cells

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pristimerin, demonstrated that BIRC5 levels may BIRC4 and BIRC3) (Ling et al., 2012). FL118 was modulate therapeutic responses, once BIRC5- able to suppress BIRC5 expression in cancer stem overexpressing prostate cancer cells became cells in a lung cancer model (Wang et al., 2017c), resistant to pristimerin (Liu et al., 2014). which are known to be a cell population that presents Salivary adenoid cystic carcinoma chemoresistance and are responsible for disease In SACC-83 salivary adenoid cystic carcinoma cells, recurrence in multiple type of cancer (Zhao, 2016). treatment with simvastatin reduced cell viability and Vaccines against BIRC5 induced apoptosis by decreasing BIRC5 levels (Cai Survivin-2B80-88 (AYACNTSTL) is an antigenic et al., 2018). peptide that can be recognized by CD8+ cells and demonstrated promising results as a potent Thyroid cancer immunogenic cancer vaccine (Idenoue et al., 2005). Nicotinamide phosphorybosiltransferase (NAMPT), By using an HLA-A24/survivin-2B80-88 tetramer, a marker for thyroid cancer that is positively the number of cytotoxic T-lymphocytes precursors associated with tumor stage and metastasis, in peripheral blood mononuclear cells of HLA-A24+ presented a positive correlation with BIRC5 cancer patients was increased. Interestingly, (survivin) and survivin splice variant º, but not with cytotoxic cells positive for this peptide were found survivin-2B, expressions, reinforcing that survivin among peripheral blood mononuclear cells obtained and its variant ΔEx3 are associated with poor from 100% of patients with breast cancers (n=7), prognosis and advanced stage cancer (Sawicka- 83% with colorectal cancers (n=7) and 57% with Gutaj et al., 2015). gastric cancers (n=7) (Idenoue et al., 2005). Urinary tract cancer Dendritic cells vaccines using recombinant BIRC5 were tested in hormone refractory prostate cancer In SK-NEP-1 Wilms tumor cells, YM155 treatment patients and results revealed cellular response, reduced cell proliferation, induced apoptosis and disease stabilization, partial tumor remission and no inhibited growth of xenograft tumors. Interestingly, adverse events (Xi et al., 2015). YM155 treatment promoted an elevation in levels of Using the DepoVax platform, a BIRC5 vaccine was other BIRC-related genes, such as BIRC3 and developed (DPX-Survivac) and produced antigen- BIRC8, suggesting that the regulation of cell death specific immune responses in ovarian cancer induced by BIRC5 suppression is highly patients. Of note, 12 out of 18 ovarian patients orchestrated with other members of the IAP family remained without clinical progression after a 6- (Tao et al., 2012). month treatment (Berinstein et al., 2015). A study using vaccination with a long BIRC5 To be noted peptide demonstrated a BIRC5-specific CD8- Pharmacological Advances for BIRC5 inhibition mediated tumor cell lysis and, more importantly, the YM155, a small-molecule BIRC5 inhibitor, was presence of circulating anti-BIRC5 antibodies was developed in 2007 and tested in multiple cancer found in both, murine glioblastoma models and models. YM155 caused a concentration-dependent human glioblastoma patients following vaccination. cytotoxic effect with IC50 values reaching nanomolar The same vaccine showed promising results in concentrations (Nakahara et al., 2007; Rauch et al., GL261 glioma and B16 melanoma murine models 2014). The mechanism of action for YM155 (Fenstermaker et al., 2018). involves a selective inhibition of BIRC5 promoter Gene Therapy targeting BIRC5 activity by disrupting Sp1 interaction in a specific Gene therapy has already been used as an approach region of the BIRC5 core promoter. Such repression for inhibiting the expression of BIRC5 and to occurs in a cell cycle-independent manner (Cheng et improve cell death induction in cancer. A combined al., 2012). gene therapy using BIRC5 siRNA and the fusion A novel survivin inhibitor developed in 2012, suicide gene yCDglyTK system displayed a relevant FL118, presents structural similarities to irinotecan. antitumor effect, inducing apoptosis more efficiently Such molecule selectively inhibits survivin promoter and eradicating colon cancer cells. Furthermore, this activity and gene expression in a TP53 status- therapeutic system was able to inhibit the migration independent manner. of colon cancer cells in vitro (Ye et al., 2017). Additionally, it promotes the inhibition of three additional cancer-associated survival genes (MCL1,

Pharmacological approaches Drug Clade Cancer type References Cheng et al., 2014; Jane Multiple cancer YM155 Small-molecule survivin inhibitor et al., 2013; Kita et al., types 2012; Lai et al., 2012

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FL118 Small-molecule survivin inhibitor Cancer Stem Cell Wang et al., 2017 Vaccines Vaccine Clade Cancer Type References Breast cancer; Survivin-2B80-88 Antigenic peptide Gastric cancer; Idonoue et al., 2005 Colorectal cancer Hormone Dendritic Cell Dendritic cells vaccines using recombinant refractory prostate Xi et al., 2015 Vaccines BIRC5 cancer patients BIRC 5 vaccine developed based on DPX-Survivac Ovarian cancer Berinstein et al., 2015 DepoVax platform Fernstermarker et al., SurVaxM Long BIRC5 peptide Gliobastoma 2018 Gene Therapy Strategy Cancer Type References Suicide gene yCDglyTK combined with BIRC5 siRNA Colon cancer cells Ye et al., 2017 Heparin-polyethyleneimine (HPEI) nanoparticles to deliver a Ovarian carcinoma Luo et al.,2016 dominant-negative human BIRC5 T34A (hs-T34A) Packaging RNA (pRNA) of bacteriophage phi29 DNA- Ovarian carcinoma Tarapore et al., 2011 packaging motor to carry BIRC 5 and methallotionein siRNA Adeno-associated virus (aaV)-mediated the dominant-negative Gastric cancer Dang et al., 2015 human BIRC5 T34A (raaV-Sur- Mut(T34a) Nanotechnology Strategy of use Nanoparticle Cancer Type References Fe3O4 core covered respectively by polyacrylate (PA) and polyethyleneimine Breast cancer Arami et al., 2016 (PEI) layer (Fe3O4-PA-PEI) Magnetic nanoparticles containing polyethyleneglycol-lactate polymer (PEG- Breast cancer and Nanoparticles for Arami et al., 2017 siRNA delivery LAC), chitosan, and polyethyleneimine Leukemia (PEI) Poly(ethylene glycol)-modified chitosan Murine breast Sun et al., 2016 (PEG-CS) cancer NDCONH(CH2)2NH-VDGR/survivin Breast cancer Bi et al., 2016 Nanoparticles for Monomethoxypolyethylene glycol-chitosan Prostate cancer Yang et al., 2015 shRNA delivery (mPEG-CS) Nanoparticles for Nanoparticles were also developed for co- Murine cancer Jin et al., 2018; Salzano combinatory delivery of siRNA targeting BIRC5 and models et al., 2015 treatment paclitaxel

Table 2. Summary of BIRC5 targeting strategies in cancer.

Gene therapy using degradable heparin- packaging RNA (pRNA) of bacteriophage phi29 polyethyleneimine (HPEI) nanoparticles to deliver a DNA-packaging motor to carry siRNA for combined dominant-negative human BIRC5 T34A (hs-T34A) BIRC5 and metallothionein silencing presented a gene was also used in ovarian cancer with promising stronger effect on reducing cell proliferation and results. HPEI nanoparticles effectively delivered the aggressiveness in ovarian tumor cell lines than either hs-T34A into ovarian carcinoma cells with low one applied alone (Tarapore et al., 2011). systemic cytotoxicity. Additionally, intraperitoneal Adeno-associated virus (aaV)-mediated the administration of HPEI/hs-T34A complexes dominant-negative human BIRC5 T34A (raaV-Sur- inhibited tumor growth in ovarian cancer xenograft Mut(T34a)) delivery inhibited cell proliferation, murine model (Luo et al., 2016). The use of induced apoptosis and sensitized gastric cancer cells

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to 5-FU in vitro and impaired tumor growth in vivo identification of aggressive ovarian carcinomas Int J Clin (Dang et al., 2015). Exp Pathol 2011 Jun 20;4(5):444-53 Nanotechonology for BIRC5 depletion Azuhata T, Scott D, Takamizawa S, Wen J, Davidoff A, Several nanotechnology-based systems were Fukuzawa M, Sandler A. The inhibitor of apoptosis protein survivin is associated with high-risk behavior of developed to improve the delivery of siRNA or neuroblastoma J Pediatr Surg 2001 Dec;36(12):1785-91 shRNA targeting BIRC5 in cancer cells, including a Bae IS, Kim CH, Kim JM, Cheong JH, Ryu JI, Han MH. Fe3O4 core covered respectively by a polyacrylate Correlation of survivin and B-cell lymphoma 2 expression (PA) or polyethyleneimine (PEI) layer (Fe3O4-PA- with pathological malignancy and anti-apoptotic properties PEI) (Arami et al., 2016). Moreover, magnetic of glial cell tumors Biomed Rep 2017 Apr;6(4):396-400 nanoparticles containing polyethyleneglycol-lactate Berinstein NL, Karkada M, Oza AM, Odunsi K, Villella JA, polymer (PEG-LAC) have also been used for such Nemunaitis JJ, Morse MA, Pejovic T, Bentley J, Buyse M, means, as well as other systems, like chitosan and Nigam R, Weir GM, MacDonald LD, Quinton T, Rajagopalan polyethyleneimine (PEI) (Arami et al., 2017), R, Sharp K, Penwell A, Sammatur L, Burzykowski T, poly(ethylene glycol)-modified chitosan (PEG-CS) Stanford MM, Mansour M. Survivin-targeted immunotherapy drives robust polyfunctional T cell (Sun et al., 2016), NDCONH(CH2) 2NH- generation and differentiation in advanced ovarian cancer VDGR/survivin (Bi et al., 2016) and patients Oncoimmunology 2015 May 7;4(8):e1026529 monomethoxypolyethylene glycol-chitosan (mPEG- Bi Y, Zhang Y, Cui C, Ren L, Jiang X. Gene-silencing effects CS) (Yang et al., 2016a). These systems have been of anti-survivin siRNA delivered by RGDV-functionalized shown to inhibit expression of BIRC5, increase nanodiamond carrier in the breast carcinoma cell line MCF- apoptosis, reduce cell proliferation and metastasis, 7 Int J Nanomedicine 2016 Nov 4;11:5771-5787 and to shrink tumor size in multiple cancer models. Brun SN, Markant SL, Esparza LA, Garcia G, Terry D, Nanoparticles were also developed for co-delivery of Huang JM, Pavlyukov MS, Li XN, Grant GA, Crawford JR, siRNA targeting BIRC5 and paclitaxel, which Levy ML, Conway EM, Smith LH, Nakano I, Berezov A, Greene MI, Wang Q, Wechsler-Reya RJ. Survivin as a constrained tumor growth, prolonged survival and therapeutic target in Sonic hedgehog-driven augmented anticancer properties of paclitaxel in medulloblastoma Oncogene 2015 Jul;34(29):3770-9 murine cancer models (Jin et al., 2018; Salzano et al., Budhidarmo R, Day CL. 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clinicopathological characteristics in colorectal neural tumor cell death through caspase-independent and - adenocarcinomas using real-time qPCR World J dependent pathways J Neurochem 2001 Oct;79(2):426-36 Gastroenterol 2011 Mar 28;17(12):1614-21 Shen X, Zheng JY, Shi H, Zhang Z, Wang WZ. Survivin Peery RC, Liu JY, Zhang JT. Targeting survivin for knockdown enhances gastric cancer cell sensitivity to therapeutic discovery: past, present, and future promises radiation and chemotherapy in vitro and in nude mice Am J Drug Discov Today 2017 Oct;22(10):1466-1477 Med Sci 2012 Jul;344(1):52-8 Premkumar DR, Jane EP, Pollack IF. Cucurbitacin-I inhibits Shi K, An J, Shan L, Jiang Q, Li F, Ci Y, Wu P, Duan J, Hui Aurora kinase A, Aurora kinase B and survivin, induces K, Yang Y, Xu C. Survivin-2B promotes autophagy by defects in cell cycle progression and promotes ABT-737- accumulating IKK alpha in the nucleus of selenite-treated induced cell death in a caspase-independent manner in NB4 cells Cell Death Dis 2014 Feb 20;5:e1071 malignant human glioma cells Cancer Biol Ther 2015;16(2):233-43 Shintani M, Sangawa A, Yamao N, Kamoshida S. Immunohistochemical expression of nuclear and Rödel F, Sprenger T, Kaina B, Liersch T, Rödel C, Fulda S, cytoplasmic survivin in gastrointestinal carcinoma Int J Clin Hehlgans S. Survivin as a prognostic/predictive marker and Exp Pathol 2013 Nov 15;6(12):2919-27 molecular target in cancer therapy Curr Med Chem 2012;19(22):3679-88 Song Z, Yao X, Wu M. Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity Raj D, Liu T, Samadashwily G, Li F, Grossman D. Survivin of survivin during taxol-induced apoptosis J Biol Chem repression by p53, Rb and E2F2 in normal human 2003 Jun 20;278(25):23130-40 melanocytes Carcinogenesis 2008 Jan;29(1):194-201 Stauber RH, Mann W, Knauer SK. Nuclear and cytoplasmic Rauch A, Hennig D, Schäfer C, Wirth M, Marx C, Heinzel T, survivin: molecular mechanism, prognostic, and therapeutic Schneider G, Krämer OH. Survivin and YM155: how faithful potential Cancer Res 2007 Jul 1;67(13):5999-6002 is the liaison? Biochim Biophys Acta 2014 Apr;1845(2):202- 20 doi: 10 Stella S, Tirrò E, Conte E, Stagno F, Di Raimondo F, Manzella L, Vigneri P. Suppression of survivin induced by a Roy K, Kanwar RK, Krishnakumar S, Cheung CH, Kanwar BCR-ABL/JAK2/STAT3 pathway sensitizes imatinib- JR. Competitive inhibition of survivin using a cell-permeable resistant CML cells to different cytotoxic drugs Mol Cancer recombinant protein induces cancer-specific apoptosis in Ther 2013 Jun;12(6):1085-98 colon cancer model Int J Nanomedicine 2015 Feb 2;10:1019-43 Stroopinsky D, Rajabi H, Nahas M, Rosenblatt J, Rahimian M, Pyzer A, Tagde A, Kharbanda A, Jain S, Kufe T, Leaf Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional RK, Anastasiadou E, Bar-Natan M, Orr S, Coll MD, Palmer and therapeutic biology of survivin Cancer Lett 2006 Dec K, Ephraim A, Cole L, Washington A, Kufe D, Avigan D. 8;244(2):164-71 MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism J Cell Mol Sajid A, Manzoor Q, Iqbal M, Tyagi AK, Sarfraz RA, Sajid A. Med 2018 May 15 Pinus Roxburghii essential oil anticancer activity and chemical composition evaluation EXCLI J 2018 Mar Sun L, Zhao Y, Shi H, Ma C, Wei L. LMP-1 induces survivin 12;17:233-245 expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma Salzano G, Navarro G, Trivedi MS, De Rosa G, Torchilin Oncol Rep 2015 May;33(5):2253-60 VP. Multifunctional Polymeric Micelles Co-loaded with Anti- Survivin siRNA and Paclitaxel Overcome Drug Resistance Sun P, Huang W, Jin M, Wang Q, Fan B, Kang L, Gao Z. in an Animal Model of Ovarian Cancer Mol Cancer Ther Chitosan-based nanoparticles for survivin targeted siRNA 2015 Apr;14(4):1075-84 delivery in breast tumor therapy and preventing its metastasis Int J Nanomedicine 2016 Sep 27;11:4931-4945 Sam MR, Tavakoli-Mehr M, Safaralizadeh R. Omega-3 fatty acid DHA modulates p53, survivin, and microRNA-16-1 Szafer-Glusman E, Fuller MT, Giansanti MG. Role of expression in KRAS-mutant colorectal cancer stem-like Survivin in cytokinesis revealed by a separation-of-function cells Genes Nutr 2018 Apr 2;13:8 allele Mol Biol Cell 2011 Oct;22(20):3779-90 Sandler A, Scott D, Azuhata T, Takamizawa S, O'Dorisio S. Tajiri T, Tanaka S, Shono K, Kinoshita Y, Fujii Y, Suita S, The survivin:Fas ratio is predictive of recurrent disease in Ihara K, Hara T. Quick quantitative analysis of gene neuroblastoma J Pediatr Surg 2002 Mar;37(3):507-11 dosages associated with prognosis in neuroblastoma Cancer Lett 2001 May 10;166(1):89-94 Sawicka-Gutaj N, Waligórska-Stachura J, Andrusiewicz M, Biczysko M, Sowiński J, Skrobisz J, Takeuchi H, Morton DL, Elashoff D, Hoon DS. Survivin Ruchańa M. Nicotinamide expression by metastatic melanoma predicts poor disease phosphorybosiltransferase overexpression in thyroid outcome in patients receiving adjuvant polyvalent vaccine malignancies and its correlation with tumor stage and with Int J Cancer 2005 Dec 20;117(6):1032-8 survivin/survivin ΔEx3 expression Tumour Biol 2015 Sep;36(10):7859-63 Tang TK, Chiu SC, Lin CW, Su MJ, Liao MH. Induction of survivin inhibition, G/M cell cycle arrest and autophagic on Serrano-López J, Serrano J, Figueroa V, Torres-Gomez A, cell death in human malignant glioblastoma cells Chin J Tabares S, Casaño J, Fernandez-Escalada N, Sánchez- Physiol 2015 Apr 30;58(2):95-103 Garcia J. Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt Tao YF, Lu J, Du XJ, Sun LC, Zhao X, Peng L, Cao L, Xiao signaling pathway and represents a favorable prognostic PF, Pang L, Wu D, Wang N, Feng X, Li YH, Ni J, Wang J, factor in patients with acute myeloid leukemia Pan J. Survivin selective inhibitor YM155 induce apoptosis Haematologica 2013 Dec;98(12):1877-85 in SK-NEP-1 Wilms tumor cells BMC Cancer 2012 Dec 26;12:619 Shankar SL, Mani S, O'Guin KN, Kandimalla ER, Agrawal S, Shafit-Zagardo B. Survivin inhibition induces human Tarapore P, Shu Y, Guo P, Ho SM. Application of phi29 motor pRNA for targeted therapeutic delivery of siRNA

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silencing metallothionein-IIA and survivin in ovarian cancers Yahya RS, Fouda MI, El-Baz HA, Mosa TE, Elmaksoud MD. Mol Ther 2011 Feb;19(2):386-94 Serum Survivin and TP53 Gene Expression in Children with Acute Lymphoblastic Leukemia Iran J Public Health Thomas J, Liu T, Cotter MA, Florell SR, Robinette K, Hanks 2012;41(1):37-44 AN, Grossman D. Melanocyte expression of survivin promotes development and metastasis of UV-induced Yamada T, Horinaka M, Shinnoh M, Yoshioka T, Miki T, melanoma in HGF-transgenic mice Cancer Res 2007 Jun Sakai T. A novel HDAC inhibitor OBP-801 and a PI3K 1;67(11):5172-8 inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma Int Tian QG, Wu YT, Liu Y, Zhang J, Song ZQ, Gao WF, Guo J Oncol 2013 Oct;43(4):1080-6 TK, He CH, Dai FR. Expressions and correlation analysis of HIF-1α, survivin and VEGF in patients with Yamanaka K, Nakahara T, Yamauchi T, Kita A, Takeuchi M, hepatocarcinoma Eur Rev Med Pharmacol Sci 2018 Kiyonaga F, Kaneko N, Sasamata M. Antitumor activity of Jun;22(11):3378-3385 YM155, a selective small-molecule survivin suppressant, alone and in combination with docetaxel in human Tsuneki M, Kinjo T, Mori T, Yoshida A, Kuyama K, Ohira A, malignant melanoma models Clin Cancer Res 2011 Aug Miyagi T, Takahashi K, Kawai A, Chuman H, Yamazaki N, 15;17(16):5423-31 Masuzawa M, Arakawa H. Survivin: A novel marker and potential therapeutic target for human angiosarcoma Yan H, Thomas J, Liu T, Raj D, London N, Tandeski T, Cancer Sci 2017 Nov;108(11):2295-2305 Leachman SA, Lee RM, Grossman D. Induction of melanoma cell apoptosis and inhibition of tumor growth Verdecia MA, Huang H, Dutil E, Kaiser DA, Hunter T, Noel using a cell-permeable Survivin antagonist Oncogene 2006 JP. Structure of the human anti-apoptotic protein survivin Nov 2;25(52):6968-74 reveals a dimeric arrangement Nat Struct Biol 2000 Jul;7(7):602-8 Yan X, Su H. YM155 Down-Regulates Survivin and Induces P53 Up-Regulated Modulator of Apoptosis (PUMA)- Vivas-Mejia PE, Rodriguez-Aguayo C, Han HD, Shahzad Dependent in Oral Squamous Cell Carcinoma Cells Med Sci MM, Valiyeva F, Shibayama M, Chavez-Reyes A, Sood AK, Monit 2017 Apr 24;23:1963-1972 Lopez-Berestein G. Silencing survivin splice variant 2B leads to antitumor activity in taxane--resistant ovarian Yang AQ, Wang PJ, Huang T, Zhou WL, Landman J. Effects cancer Clin Cancer Res 2011 Jun 1;17(11):3716-26 of monomethoxypolyethylene glycol-chitosan nanoparticle- mediated dual silencing of livin and survivin genes in Wang D, Jiao C, Zhu Y, Liang D, Zao M, Meng X, Gao J, He prostate cancer PC-3M cells Genet Mol Res 2016 Apr Y, Liu W, Hou J, Zhong Z, Cheng Z. Activation of 4;15(2) CXCL12/CXCR4 renders colorectal cancer cells less sensitive to radiotherapy via up-regulating the expression of Yang H, Du X, Xi Y. Effects of survivin on FVADT survivin Exp Biol Med (Maywood) 2017 Feb;242(4):429- chemotherapy for refractory multiple myeloma Exp Ther 435 Med 2016 Aug;12(2):771-776 Wang H, Li S, Luo X, Song Z, Long X, Zhu X. Knockdown Yang M, Liu Y, Lu S, Wang Z, Wang R, Zi Y, Li J. Analysis of PARP6 or survivin promotes cell apoptosis and inhibits of the expression levels of survivin and VEGF in patients cell invasion of colorectal adenocarcinoma cells Oncol Rep with acute lymphoblastic leukemia Exp Ther Med 2013 2017 Apr;37(4):2245-2251 Jan;5(1):305-307 Wang J, Liu Z, Zhang D, Liu R, Lin Q, Liu J, Yang Z, Ma Q, Ye L, Yang Y, Ma XY, Li D, Xu ML, Tan P, Long LM, Wang Sun D, Zhou X, Jiang G. FL118, a novel survivin inhibitor, HQ, Liu T, Guo YH. Construction of a novel vector wins the battle against drug-resistant and metastatic lung expressing Survivin-shRNA and fusion suicide gene cancers through inhibition of cancer stem cell-like properties yCDglyTK and its application in inhibiting proliferation and Am J Transl Res 2017 Aug 15;9(8):3676-3686 migration of colon cancer cells Exp Ther Med 2017 Nov;14(5):4721-4728 Wang Q, Chen Z, Diao X, Huang S. Induction of autophagy- dependent apoptosis by the survivin suppressant YM155 in Yen CS, Choy CS, Huang WJ, Huang SW, Lai PY, Yu MC, prostate cancer cells Cancer Lett 2011 Mar 1;302(1):29-36 Shiue C, Hsu YF, Hsu MJ. A Novel Hydroxamate-Based Compound WMJ-J-09 Causes Head and Neck Squamous Wang S, Xu J, Zhang Q. Clinical significance of survivin Cell Carcinoma Cell Death via LKB1-AMPK-p38MAPK-p63- and vascular endothelial growth factor mRNA detection in Survivin Cascade Front Pharmacol 2018 Mar 1;9:167 the peripheral whole blood of breast cancer patients Neoplasma 2016;63(1):133-40 Yu X, Zhang Y, Cavazos D, Ma X, Zhao Z, Du L, Pertsemlidis A. miR-195 targets cyclin D3 and survivin to Wang X, Qiu W, Zhang G, Xu S, Gao Q, Yang Z. MicroRNA- modulate the tumorigenesis of non-small cell lung cancer 204 targets JAK2 in breast cancer and induces cell Cell Death Dis 2018 Feb 7;9(2):193 apoptosis through the STAT3/BCl-2/survivin pathway Int J Clin Exp Pathol 2015 May 1;8(5):5017-25 Zeng W, Meng F, Liu Z, Mao X, Luo L, Zheng M, Qin S, Liu W, Zhou J, Sun H, Huang L. Bortezomib-based Weng G, Zeng Y, Huang J, Fan J, Guo K. Curcumin chemotherapy regimens can improve response in newly Enhanced Busulfan-Induced Apoptosis through diagnosed multiple myeloma patients with bcl-2 and survivin Downregulating the Expression of Survivin in Leukemia overexpression Int J Clin Exp Pathol 2014 Jun Stem-Like KG1a Cells Biomed Res Int 2015;2015:630397 15;7(7):4239-46 Xi HB, Wang GX, Fu B, Liu WP, Li Y. Survivin and PSMA Zhang J, Zhu Z, Sun Z, Sun X, Wang Z, Xu H. Survivin gene Loaded Dendritic Cell Vaccine for the Treatment of Prostate expression increases gastric cancer cell lymphatic Cancer Biol Pharm Bull 2015;38(6):827-35 metastasis by upregulating vascular endothelial growth Xu S, Adisetiyo H, Tamura S, Grande F, Garofalo A, Roy- factor-C expression levels Mol Med Rep 2014 Burman P, Neamati N. Dual inhibition of survivin and MAOA Feb;9(2):600-6 synergistically impairs growth of PTEN-negative prostate Zhang L, Zhang W, Wang YF, Liu B, Zhang WF, Zhao YF, cancer Br J Cancer 2015 Jul 14;113(2):242-51 Kulkarni AB, Sun ZJ. Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck

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squamous cell carcinoma Cell Death Dis 2015 May poor prognostic marker in pancreatic ductal 28;6:e1771 adenocarcinoma J Surg Oncol 2018 Dec;118(7):1115-1121 Zhang Y, Chen HX, Zhou SY, Wang SX, Zheng K, Xu DD, Zhu J, Sun C, Wang L, Xu M, Zang Y, Zhou Y, Liu X, Tao Liu YT, Wang XY, Wang X, Yan HZ, Zhang L, Liu QY, Chen W, Xue B, Shan Y, Yang D. Targeting survivin using a WQ, Wang YF. Sp1 and c-Myc modulate drug resistance of combination of miR494 and survivin shRNA has synergistic leukemia stem cells by regulating survivin expression effects on the suppression of prostate cancer growth Mol through the ERK-MSK MAPK signaling pathway Mol Cancer Med Rep 2016 Feb;13(2):1602-10 2015 Mar 7;14:56 Zhuo W, Zhang L, Zhu Y, Zhu B, Chen Z. Fisetin, a dietary Zhang Y, Wang J, Sui X, Li Y, Lu K, Fang X, Jiang Y, Wang bioflavonoid, reverses acquired Cisplatin-resistance of lung X. Prognostic and Clinicopathological Value of Survivin in adenocarcinoma cells through MAPK/Survivin/Caspase Diffuse Large B-cell Lymphoma: A Meta-Analysis Medicine pathway Am J Transl Res 2015 Oct 15;7(10):2045-52 (Baltimore) 2015 Sep;94(36):e1432 de Almagro MC, Vucic D. The inhibitor of apoptosis (IAP) Zhao J. Cancer stem cells and chemoresistance: The proteins are critical regulators of signaling pathways and smartest survives the raid Pharmacol Ther 2016 targets for anti-cancer therapy Exp Oncol 2012 Apr;160:145-58 Oct;34(3):200-11 Zheng WY, Kang YY, Li LF, Xu YX, Ma XY. Levels of de Graaff MA, Malu S, Guardiola I, Kruisselbrink AB, de effectiveness of gene therapies targeting survivin and its Jong Y, Corver WE, Gelderblom H, Hwu P, Nielsen TO, splice variants in human breast cancer cells Drug Discov Lazar AJ, Somaiah N, Bovée JVMG. High-Throughput Ther 2011 Dec;5(6):293-8 Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth Transl Oncol 2017 Zhou H, Mak PY, Mu H, Mak DH, Zeng Z, Cortes J, Liu Q, Aug;10(4):546-554 Andreeff M, Carter BZ. Combined inhibition of β-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor- This article should be referenced as such: resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo Leukemia 2017 Branco PC, Jimenez PC, Machado-Neto JA, Costa- Oct;31(10):2065-2074 Lotufo LV. BIRC5 (baculoviral IAP repeat containing 5). Atlas Genet Cytogenet Oncol Haematol. 2019; Zhou L, Lu J, Liang ZY, Zhou WX, Yuan D, Li BQ, You L, 23(7):168-186. Guo JC, Zhao YP. High nuclear Survivin expression as a

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Gene Section Short Communication

SLC45A2 (solute carrier family 45 member 2) Mainak Sengupta, Tithi Dutta, Kunal Ray University of Calcutta, Department of Genetics, 35, Ballygunge Circular Road, Kolkata - 700 019, India. [email protected]; [email protected] (MS, TD) ATGC Diagnostics Private Limited, Kolkata, India, [email protected] (KR)

Published in Atlas Database: January 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC45A2ID41306ch5p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70469/01-2019-SLC45A2ID41306ch5p13.pdf DOI: 10.4267/2042/70469 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

33,985,144(GRCh38/hg38). Orientation: Minus Abstract strand. It contains 7 exons. SLC45A2 gene, having a chromosomal location Transcription 5p13.2, encodes a membrane associated transporter protein (MATP). MATP is a transmembrane protein. The gene after transcription produces 7 different It is present in the melanosomal membrane in the mRNAs, 6 alternatively spliced variants and 1 melanocytes. It maintains the osmotic potential by unspliced form. There are 4 non overlapping regulating the pH of the melanosomal lumen. alternative last exons Defects in the SLC45A2 gene causes (https://www.ncbi.nlm.nih.gov/IEB/Research/Acem oculocutaneous albinism type IV; OCA IV bly/av.cgi?db=humanterm=slc45a2submit=Go). Keywords Protein SLC45A2, MATP, albinism, OCA IV Description Identity The human SLC45A2 protein is a 530-amino acid Other names: AIM1, SHEP5; OCA4 polypeptide that contains 12 putative transmembrane domains, and is only expressed in the HGNC (Hugo): SLC45A2 melanosomes in the melanocytes (Newton et al., Location: 5p13.2 2001). The SLC45A2 gene initially identified as AIM1 DNA/RNA (absent in melanoma 1) by Newton et al, 2001 encodes a Membrane-Associated Transporter Description Protein (MATP). It acts as a transporter and In Chromosome 5, the 40,529 bases of DNA starts regulates the melanosomal pH using a proton from 33,944,616 and ends at gradient.

Figure 1. SLC45A2 Gene in genomic location: Cytogenetic band: 5p13.2 by Entrez Gene, 5p13.2 by HGNC, 5p13.2. The figure represents the cytogenetic banding of SLC45A2 locus (Ref https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC45A2)

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 187 SLC45A2 (solute carrier family 45 member 2) Sengupta M et al.

Figure 2. The SLC45A2 (MATP) acts as a transporter present on the melanosomal membrane. Under normal condition it controls the pH by using a proton gradient. Thus helps in Copper to bind to Apo-Tyrosinase and convert it to active Tyrosinase. In oculocutaneous albinism type IV (OCA4), any deleterious mutation in melanosomal MATP transporter protein makes the melanosomal lumen acidic. Under this condition, the Cu fails to bind to the Apo-Tyr and Tyrosinase activity is reduced. (Bin et al, 2015). Expression Germinal The MATP protein (58 kDa) is expressed in most Homozygous mutation or Compound Heterozygote melanoma cell lines and melanocytes and sorted into mutations in SLC45A2 gene has been found the melanosomal membrane. The highest expression responsible for causing Oculocutaneous Albinism level has been observed in the pigmented layer of Type 4 (OCA4). To date around 80 mutations have retina (https://www.uniprot.org/uniprot/Q9UMX9). been reported in SLC45A2 responsible for OCA4. Localisation (Kamaraj et al. 2014, Toth et al. 2017). OCA4 was first observed in Turkish population, it is rare among It is a transmembrane protein present in the Caucasians and Africans and in Japan it is diagnosed melanosomal membrane in melanin producing in one of four persons affected with OCA. melanocytes. There are several non-pathogenic polymorphisms Function which result into mild pigmentation. The haplotypes at SLC45A2 is significantly SLC45A2 (MATP) allows the transport of sugar associated in determination of dark or light molecule across the membrane into the cytoplasm pigmentation features in human population. and maintains osmotic potential of the melanosomes (Fracasso et al.2017) (Rabea Bartolke, 2014, Reinders et al 2015). It maintains the pH of the melanosome which Epigenetics facilitates the binding of Copper to Tyrosinase In an attempt to identify genetic and epigenetic resulting in the conversion of Apo-Tyrosinase to marks involved in population structure, a coding Tyrosinase. (Newton et al, 2011). SNP: rs16891982 (p.L374F) of SLC45A2, known to play a role in normal pigmentation variation, was Homology found to positively correlate with the methylation The human MATP shows syntenic homology with level of PM20D1 gene. The minor allele A was been the proximal region of mouse chromosome 15. The found to be associated with lower methylation of the human orthologue for the mouse underwhite gene target gene. locus (uw gene) is encoded by SLC45A2 gene. The (https://www.ncbi.nlm.nih.gov/pubmed/20949057). predicted mouse MATP protein is 82% identical and 87% similar to the human MATP protein. Implicated in The highest degree of homology was found between MATP and sucrose/proton symporters found in Oculocutaneous albinism type IV plants. The homologous region of MATP includes (OCA IV) the sucrose-transporter signature sequence: R-X-G- Disease R-[K/R], found in between the transmembrane OCA IV is an autosomal recessive disorder of domains 2 and 3 (Meyer H et al, 2011, Newton et al, melanin biosynthesis that results in congenital 2011). hypopigmentation of ocular and cutaneous tissues. The sucrose transporter Slc45-1 in Drosophila shows Common developmental abnormalities of the eye significant similarity to mammalian SLC45A2 and like decreased visual acuity, macular hypoplasia, plays a role in melanin synthesis. optic dysplasia, atypical choroidal vessels, and nystagmus are observed in patient suffering from Mutations OCA type IV.

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SLC45A2 (solute carrier family 45 member 2) Sengupta M et al.

The severity of hypopigmentation is correlated with Bartölke R, Heinisch JJ, Wieczorek H, Vitavska O. Proton- melanosome size, shape, melanin content and associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae. maturity of the melanosomal structures Biochem J. 2014 Dec 1;464(2):193-201 demonstrating that the encoded protein is a major Bin BH, Bhin J, Yang SH, Shin M, Nam YJ, Choi DH, Shin determinant of mammalian pigmentation. DW, Lee AY, Hwang D, Cho EG, Lee TR. Membrane- Melanoma Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity. PLoS In 2017, Park et al reported that a few variants One. 2015;10(6):e0129273 present in SLC45A2 gene can be a promising Kamaraj B, Purohit R. Mutational analysis of immune therapeutic target for melanoma with high oculocutaneous albinism: a compact review. Biomed Res tumor selectivity and reduced potential for Int. 2014;2014:905472 autoimmune toxicity. Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton It is associated with an increased risk for melanoma HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, in light-skinned populations, and the encoded Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao protein can elicit immune recognition. W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, The Cancer Genome Atlas Research Network Canfield VA, Cheng KC. SLC24A5, a putative cation (TCGA) database reported that it is expressed by exchanger, affects pigmentation in zebrafish and humans. approximately 80% of cutaneous melanomas. Science. 2005 Dec 16;310(5755):1782-6 In the same year Hafner et al showed that SLC45A2 Meyer H, Vitavska O, Wieczorek H. Identification of an (also called AIM1, absent in melanoma 1) function animal sucrose transporter. J Cell Sci. 2011 Jun 15;124(Pt as a key suppressor of invasive phenotypes by 12):1984-91 working in association with the actin cytoskeleton. Newton JM, Cohen-Barak O, Hagiwara N, Gardner JM, SLC45A2 becomes dysregulated and suppresses Davisson MT, King RA, Brilliant MH. Mutations in the human cytoskeletal remodelling in primary and metastatic orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am J Hum prostate cancer and in non-malignant prostate Genet. 2001 Nov;69(5):981-8 epithelial cells. In 2012, Fernandez et al reported in a family that Reinders A, Ward JM. Investigating polymorphisms in membrane-associated transporter protein SLC45A2, using adult siblings presented with congenital neutropenia sucrose transporters as a model. Mol Med Rep. 2015 which later developed into Crohn's Disease. Jul;12(1):1393-8 Molecular characterisation revealed homozygous Tóth L, Fábos B, Farkas K, Sulák A, Tripolszki K, Széll M, mutations both in G6PC3 and SLC45A2 in the sister Nagy N. Identification of two novel mutations in the and mutation in single allele for both genes in the SLC45A2 gene in a Hungarian pedigree affected by unusual brother. OCA type 4. BMC Med Genet. 2017 Mar 15;18(1):27 This article should be referenced as such: References Sengupta M, Dutta T, Ray K. SLC45A2 (solute carrier family 45 member 2). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):187-189.

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Leukaemia Section Short Communication

Burkitt's lymphoma (BL) Luis Miguel Juárez Salcedo, Ana Corazón Monzón, Samir Dalia Principe de Asturias University Hospital, Madrid, Spain (LMJS); Clinic Valladolid University Hospital, Valladolid, Spain (ACM); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA [email protected] (SD).

Published in Atlas Database: January 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BurkittID2077.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70470/01-2018-BurkittID2077.pdf DOI: 10.4267/2042/70470 This article is an update of : Cuneo A, Castoldi GL. Burkitt's lymphoma (BL). Atlas Genet Cytogenet Oncol Haematol 2001;5(2)

MYC protein modulates the expression of target Abstract genes that regulate many cell processes including cell growth, division, metabolism and apoptosis. Review on Burkitt's lymphoma, with data on clinics, Chronic Epstein-Barr virus (EVB) infection appears and the genes involved. to play a role in all cases of endemic BL and minority Keywords of sporadic and immunodeficiency-associated BL Burkitt's lymphoma; MYC; IGH; IGK; IGL (Klapproth and Wirth, 2010). Identity Epidemiology Most common in children (1/3 of lymphomas). Other names: Burkitt's tumor; Malignant Endemic BL is mainly confined to equatorial Africa lymphoma Burkitt's type where it accounts for 30-50% of all childhood cancers diagnosed each year (3-6 cases per 100.000 Clinics and pathology children). Sporadic variant is mostly seen in the US and Phenotype/cell stem origin Western Europe. 30% of pediatric lymphomas and Pan-B antigens positive (CD19, CD20, CD21, CD22 3 distinct peaks at around age 10, 40 and in the and CD79a); co-expression of CD10 and Bcl-6. elderly. In all groups, most patients are male with a TdT-, CD5-, CD23-, Bcl-2- and CD138-; sIgM+. 3:1 or 4:1 male to female ratio (Magrath, 2012). The cell of origin is a peripheral IgM+ memory B- Clinics cell (presence of somatic hypermutation of the Ig gene). Ki67 expression is close to 100% of African endemic variant usually develops in neoplastic cells. children with a jaw or facial bone tumor; initial involvement of the abdomen is less common. Etiology The primary tumor can spread to mesentery, ovary, Burkitt lymphoma (BL) originates from germinal or testis, kidney, breast, and meninges, spreading to post-germinal center B cells. The three clinical lymph nodes, mediastinum, and spleen less subtypes are: endemic, sporadic and frequently. immunodeficiency-related. All of these likely arise The non-endemic variant may be associated with from B cells at different stages of development. immunodeficiency states and usually presents with The development of BL is dependent upon the abdominal involvement (distal ileum, ciecum, constitutive expression of the MYC proto-oncogene mesentery). Presenting symptoms can be related to located at chromosome 8q24. The transcription of bowel obstruction or gastrointestinal bleeding,

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 190 Burkitt's lymphoma (BL) Juárez Salcedo LM et al.

mimicking acute appendicitis or intussusception. prevention of central nervous system disease. Lymphadenopathy is generally localized. In patients younger than 60 years of age, including The disease is very aggressive and requires prompt those with well-controlled HIV, and those up to 70 treatment with appropriate regimens. years of age with good baseline functional status, Cytology CODOX-M is recommended. Patients with extensive disease and elevated LDH, 2 The blast cells in the peripheral blood and bone cycles each of R-CODOX-M and R-IVAC can be marrow display a basophilic cytoplasm with used. characteristic vacuolization, a picture For patients with low-risk disease (a single site of indisinguishable from acute lymphoblastic leukemia disease and normal LDH) 3 cycles of R-CODOX-M. (ALL) L3 of the FAB classification, which For patients with preexisting organ dysfunction, or represents the leukemic counterpart of BL. significant comorbidities and patients older than 60 WHO recognize three different types of Burkitt years of age with low-risk disease, DA-REPOCH Lymphoma: could be considering a great option associated with Classic Burkitt lymphoma: Characterized for the IT therapy or systemic methotrexate upon the monomorphic medium-size blast proliferation, with completion of cycle 6. lax chromatin, multiple nucleolis and intense The addition of rituximab to hyper-CVAD may basophilic cytoplasm. improve outcome in adult BL or B-ALL, particularly Plasmablastic Burkitt Lymphoma and Atypical in elderly patients (Castillo et al., 2013; Jacobson Burkitt lymphoma: Cells with nuclear and LaCasce, 2014; Dozzo et al., 2016). pleomorphism and nucleoli of big size but in inferior number to the observed in the classic form. Evolution The three variants, blastic cells can be associated Apart from the occasional refractory case, a few with plenty mitotic images. responsive BL patients will relapse soon after Pathology treatment completion and generally within the first 6 months of follow-up. The tumor mass demonstrate complete effacement of Results in refractory/relapsed BL are extremely the normal architecture by sheets of atypical poor, and new options are urgently needed. lymphoid cells. Relapse and progression frequency varies according At low power, the tumor has a 'mouth-eaten' to first-line treatment used. appearance, often with interspersed areas of In chemoresistant disease cases, experimental coagulative necrosis or hemorrhage. High rate of therapies, due to the globally poor results of proliferation and high rate of apoptotic cell death is traditional salvage programs, should be considered observed. A classic 'starry-sky' pattern is usually in all refractory or relapsed cases. present, imparted by numerous benign macrophages that have ingested apoptotic tumor cells. The benign Prognosis histiocytes are large with abundant, clear cytoplasm If treated promptly with appropriate regimens the and are dispersed throughout of basophilic tumor majority of patients can be cured. cells. At high power, classically are monomorphic, medium-size cells with round nuclei, multiple dark Cytogenetics nucleoli, and basophilic cytoplasm. Cytogenetics morphological The related form 'Burkitt-like' lymphoma shows intermediate features between diffuse large cell The molecular hallmark of BL is the translocation of lymphoma and BL and probably includes different the MYC proto-oncogene to the Ig heavy or 1 light disease entities. It was suggested by the WHO panel chain genes, leading to constitutive MYC activation. that only those cases with MYC rearrangement In classic BL, either endemic type or sporadic type, and/or a >99% proliferation fraction as demonstrated 90-95% of Ig loci are involved, 85% for t(8:14)/ IgH- by Ki-67 positivity should be classified as Burkitt- MYC, 10% for t(8;22)(q24;q11) /Ig-lambda /MYC like lymphoma. and approximately 5% for t(2;8)(p12;q24) /Ig- kappa/MYC. Treatment In the Burkitt-like form there are at least 3 Aggressive regimens specifically designed for this cytogenetic categories: one with an 8q24/MYC lymphoma must be used. translocation, one with an 8q24 and 18q21/ BCL2 Multiple intensive regimens demonstrate excellent translocation and another with "miscellaneous" activity in BL and are composed of doxorubicin, rearrangements, frequently including an 18q21 break alkylators, vincristine, and etoposide combined with (Bellan et al., 2005). therapy directed at the eradication and/or

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Additional anomalies Bellan C, Lazzi S, Hummel M, Palummo N, de Santi M, Amato T, Nyagol J, Sabattini E, Lazure T, Pileri SA, Raphael Recurrent chromosome aberrations associated with M, Stein H, Tosi P, Leoncini L. Immunoglobulin gene the 8q24 translocations include 1q21-25 analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas. Blood. 2005 Aug duplications, deletions of 6q11-14, 17p deletions and 1;106(3):1031-6 trisomy 12, +7, +8 and +18. Castillo JJ, Winer ES, Olszewski AJ. Population-based prognostic factors for survival in patients with Burkitt Genes involved and lymphoma: an analysis from the Surveillance, Epidemiology, and End Results database. Cancer. 2013 proteins Oct 15;119(20):3672-9 MYC Gaidano G. Molecular genetics of malignant lymphoma. In: Fo R (ed): Reviews in clinical and experimental hematology. Location 8q24.21 Forum Service Editore, Genova and Martin Dunitz, London,. Protein 1997. Catalogue of chromosome aberrations in cancer (5th edition). Mitelmam F ed Wiley Liss, New York. 1994. MYC functions as a transcriptional regulator. MYC binds to MAX that is an obligate heterodimeric Gibbs RF. The present and future medicolegal importance of record keeping in anesthesia and intensive care: the case partner for MYC in mediating its functions. for automation J Clin Monit 1989 Oct;5(4):251-5 The MYC-MAX complex is a potent activator of transcription. Thousands of MYC target genes have Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health been identified. Genes targeted by MYC include Organization classification of neoplastic diseases of the mediators of metabolism, biosynthesis, and cell hematopoietic and lymphoid tissues: report of the Clinical cycle progression (Mohamed 2017). Advisory Committee meeting-Airlie House, Virginia, November 1997 J Clin Oncol 1999 Dec;17(12):3835-49 IGH Havelange V, Pepermans X, Ameye G, Théate I, Callet- Location 14q32.33 Bauchu E, Barin C, Penther D, Lippert E, Michaux L, Mugneret F, Dastugue N, Raphaül M, Vikkula M, Poirel HA. Note Genetic differences between paediatric and adult Burkitt Alternatively: IGK, located in 2p11.2 or IGL, lymphomas Br J Haematol 2016 Apr;173(1):137-44 located in 22q11.22 Hecht JL, Aster JC. Molecular biology of Burkitt's lymphoma Result of the chromosomal J Clin Oncol 2000 Nov 1;18(21):3707-21 Jacobson C, LaCasce A. How I treat Burkitt lymphoma in anomaly adults Blood 2014 Nov 6;124(19):2913-20 Klapproth K, Wirth T. Advances in the understanding of Fusion protein MYC-induced lymphomagenesis Br J Haematol 2010 May;149(4):484-97 Oncogenesis Constitutive expression of MYC is crucial for the Kornblau SM, Goodacre A, Cabanillas F. Chromosomal abnormalities in adult non-endemic Burkitt's lymphoma and pathogenesis of BL, this protein being a key leukemia: 22 new reports and a review of 148 cases from transcriptional regulator, controlling cell the literature Hematol Oncol 1991 Mar-Apr;9(2):63-78 proliferation, differentiation and death. Macpherson N, Lesack D, Klasa R, Horsman D, Connors The deregulated expression of MYC, caused by the JM, Barnett M, Gascoyne RD. Small noncleaved, non- 8q24 translocations, is achieved through multiple Burkitt's (Burkit-Like) lymphoma: cytogenetics predict mechanisms: a) juxtaposition to regulatory elements outcome and reflect clinical presentation J Clin Oncol 1999 of the Ig loci, b) mutations in the MYC 5' regulatory May;17(5):1558-67 regions and, c) aminoacid substitutions occurring in Mohamed AN. MYC (MYC proto-oncogene, bHLH exon 2, making the MYC transactivation domain less transcription factor) Atlas Genet Cytogenet Oncol susceptible to modulation (Hecht and Aster, 2000). Haematol. in press. On line version : http://AtlasGeneticsOncology.org/Genes/MYCID27.html Additional gene alterations include the following: truncating mutations of ARID1A and amplification Polito P, Cilia AM, Gloghini A, Cozzi M, Perin T, De Paoli P, Gaidano G, Carbone A. High frequency of EBV association of MCL1; point mutations of LRP6; truncating with non-random abnormalities of the chromosome region alterations of LRP1B, PTPRD, PTEN, NOTCH1, 1q21-25 in AIDS-related Burkitt's lymphoma-derived cell and ATM; amplifications of RAF1, MDM4, MDM2, lines Int J Cancer 1995 May 4;61(3):370-4 KRAS, IKBKE, and CDK6; deletion of CDKN2A; overexpression ofMIR17HG; activating mutations of TCF3 and/or inactivating mutations of its negative regulator ID3; and CCND3 activating mutations Schlegelberger B, Zwingers T, Harder L, Nowotny H, (Havelange et al., 2016). Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Müller-Hermelink K, Feller A, Heinz R. Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell References lymphoma Kiel-Wien-Lymphoma Study Group Blood

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Siebert R, Matthiesen P, Harder S, Zhang Y, Borowski A, This article should be referenced as such: Zühlke-Jenisch R, Metzke S, Joos S, Weber-Matthiesen K, Grote W, Schlegelberger B. Application of interphase Juárez Salcedo LM, Corazón Monzón A, Dalia S. Burkitt's lymphoma (BL). Atlas Genet Cytogenet Oncol fluorescence in situ Hybridization for the detection of the Haematol. 2019; 23(7):190-193. Burkitt translocation t(8;14)(q24;q32) in B-cell lymphomas Blood 1998 Feb 1;91(3):984-90

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 193 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Leukaemia Section Review t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2 Daniel Martinez-Anaya, Rocio Juárez-Velázquez, Dafné Moreno-Lorenzana, Patricia Pérez-Vera Laboratorio de Genética y Cáncer. Instituto Nacional de PediatrÍa (DMA, RJV, PPV), Posgrado en Ciencias Biolgicas, Universidad Nacional Autnoma de México (DMA), Cátedra CONACYT-Instituto Nacional de PediatrÍa (DML); [email protected]

Published in Atlas Database: December 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0X14p22q32IGHCRLF2ID1769.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70471/12-2017-t0X14p22q32IGHCRLF2ID1769.pdf DOI: 10.4267/2042/70471 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

children and adolescents (1-18 years-old) the higher Abstract incidence of IGH/CRLF2 in patients with median Review on t(X;14)(p22;q32) or t(Y;14)(p11;q32) age of 14 years (Schmäh et al. 2017). Another report with data on the genes involved, and clinics. describes a cohort of pre B-ALL patients, ranging Keywords from 1-60 years-old, with IGH/CRLF2 in 37.2% of cases (Russell et al. 2017). In general, the prevalence IGH; CRLF2, B cell precursor Acute Lymphoblastic of IGH/CRLF2 increases with age. Leukemia (ALL), Ph-like, BCR/ABL1ñlike ALL. Clinics Clinics and pathology ALL with BCP immunophenotype with Disease rearrangement involving a cytokine receptor, included in the BCR/ABL1ñlike ALL subgroup. Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR/ABL1ñlike (Arber et al. Treatment 2016) The IGH/CRLF2 translocation results in kinase- Etiology activating lesion that causes the constitutive The translocation IGH/CRLF2 involves a CpG break activation of the Jak2/STAT5 signalling pathway. at CRLF2 and a V(D)J break at IGH locus, and The patients that harbour IGH/CRLF2 ALL could produce overexpression of the CRLF2 protein benefit from the treatment with Ruxolitinib, which (Schmäh et al. 2017). blocks Jak2/STAT5 pathway (Figure 5). This treatment could potentially improve their Epidemiology survival (Harrison 2013)). Reports about the IGH/CRLF2 prevalence have been obtained from selected and unselected patients, Prognosis mostly from retrospective cohorts; as a consequence IGH/CRLF2 is associated with high risk National contrasting results have been informed. The Medical Cancer Institute (NCI) characteristics in contrast to Research Council (MRC) found IGH/CRLF2 in 1% P2RY8/CRLF2 positive patients. IGH/CRLF2 is of paediatric patients (Ensor et al. 2011); in adults also present in patients with high levels of minimal with Ph-like this translocation has been detected in residual disease (MRD) (≥ 10-3) which are consider 57.6% of cases (Roberts et al. 2017). A recent study MRD-slow early responders, based on this the group reports in ALL is prone to suffer relapses (Schmäh et al. 2017; Attarbaschi et al. 2012).

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Figure 1. CRLF2 Flow cytometry analysis in an ALL patient with IGH/CRLF2 rearrangement. The figure shows the strategy applied to analyze by flow cytometry the CRLF2 overexpression and activation in blasts population (CD34+ CD19+), compared with unstained control (A). In this patient almost 100% of blasts are positive to CRLF2 protein, (B) and its signaling pathway is active since the phosphorylation of STAT5 at tyrosine residue (pY694) is present and (C) was reversible by the Jak2 inhibitor Ruxolitinib.

Figure 2. Chromosomes obtained from MHH-CALL-4 cell line positive to IGH/CRLF2 translocation detected by fluorescence in situ hybridization (FISH). The der(Y) chromosome is lost in the cell line. (A) Metaphase hybridized with CRLF2 break-apart probe (Cytocell Aquarius) with a normal chromosome X (yellow arrow) and the der(14) (green arrow). (B) Metaphase hybridized with IGH break-apart probe (Vysis-Abbott) with the normal chromosome 14 (yellow arrow) and the der(14) (red arrow). IGH/CRLF2 positive cells also have a high Cytogenetics frequency (94%) of additional deletions which may reflect chromosomal instability (Schmäh et al. Cytogenetics morphological 2017). t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2 The most common deletions in addition to this is a cryptic rearrangement (Figures 2 and 3). It is rearrangement are found in IKZF1 (53%), ADD3 present in patients with extra copies of the X (46%) and SLX4IP (41%). Similar to patients chromosome produced by high hyperdiploidy in P2RY8/CRLF2 positive, deletions in JAK1/ JAK2 19.8% of cases. To date, only one patient who (17%) are also present (Russell et al. 2017). presented both a PAR1 deletion (P2RY8/CRLF2) Although IGH/CRLF2 is part of the BCR/ABL1-like and IGH/CRLF2 translocation has been reported ALL subtype this rearrangement is not associated (Harvey et al. 2010). Recently, two patients with with it in all cases; however, those patients with the coexistence of IGH/CRLF2 and BCR/ ABL1 rearrangement in coexistence with JAK2 mutations rearrangements have been described. One patient have been found that present the expression presented both rearrangements in different clones signature of the subtype (Herold et al. 2017). (Russell et al. 2017); the other case showed the Although in Down syndrome patients the translocation t(Y;14) harbouring the CRLF2 P2RY8/CRLF2 deletion is more frequent, rearrangement in 90% of interphases, and presented IGH/CRLF2 rearrangement is also observed (35% BCR/ABL1 fusion in a subset of the CRLF2- vs. 20% respectively) (Russell et al. 2017). rearranged cells (Jain et al. 2017).

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Figure 3. (A-B) FISH in interphase nuclei with the IGH break apart-probe, and (C-D) with the CRLF2 break-apart probe. The yellow arrows indicate normal alleles and the red and green arrows indicate monoallelic breakages.

transcript variant 2 has 1503pb mRNA Genes involved and NM_001012288.2, this variant lacks an alternate proteins exon which results in translation initiation at a downstream start codon compared to variant 1, the IGH (immunoglobulin heavy locus) resulting isoform is shorter at the N-terminus Location compared to isoform 1(Russell et al. 2017); the 14q32.33 transcript variant 3, uses an alternative splice Protein-coding gene. Others names: D (diversity) junction at the 5¥end of an exon, and contains region of heavy chains; J (joining) region of heavy another alternate exon compared to variant 1, this chains; immunoglobulin heavy chain variable variant is a non-coding mRNA NR_110830.1. region; immunoglobulin heavy diversity group; Protein immunoglobulin heavy diversity locus; The cytokine receptor-like factor 2 has a size of 371 immunoglobulin heavy joining cluster; amino acids, with a molecular mass of 42013 immunoglobulin heavy joining group; Daltons. Cytokine receptor-like factor 2 is a immunoglobulin heavy polypeptide, joining region; transmembrane protein with an extracellular domain immunoglobulin heavy variable cluster; of 210 residues, and an intracellular domain of 119 immunoglobulin heavy variable group. Other residues (Zhang et al. 2001). CRLF2 symbols: IGHDY1; IGH@; IGD1; IGHV; IGHD@; heterodimerizes with IL7R constituting a functional IGHJ@; IGHV@; IGH1@ receptor (Figure 5) (Rochman et al. 2010; Bugarin et DNA/RNA al. 2015). The genomic location of IGH starts at 105,536,746 Somatic mutations pb from 14pter and ends in 106,879,844pb from The CRLF2 711T>G (Phe232Cys) mutation has 14pter. The size is 1,343,098 bases, with minus been found in ALL blasts. The CRLF2 Phe232 strand orientation NC_000014.9 residue is near to the junction of the extracellular and CRLF2 (cytokine receptor like factor transmembrane domains. The Phe232Cys mutation confers a constitutive dimerization through the 2) cysteine residues inducing cell growth. This Location mutation also promotes the up-regulation of It is located at the PAR1 of chromosome X, downstream transcriptional targets of the Xp22.33, and chromosome Y, Yp11. Jak2/STAT5 pathway (Figure 5) (Yoda et al. 2010). Protein-coding gene. Other names and symbols: Thymic Stromal Lymphopoietin Protein Receptor, Result of the chromosomal TSLP Receptor, Thymic Stromal-Derived Lymphopoietin Receptor, Cytokine Receptor-Like anomaly 2. Others symbols: TSLPR, CRL2, CRLF2Y. Hybrid gene DNA/RNA The genomic location of CRLF2 gene in The IGH/CRLF2 rearrangement results from a chromosome X starts at 1,187, 549 bp from Xpter, cryptic translocation t(X;14)(p22;q32) or and ends at 1, 212, 815 bp from Xpter. The size is t(Y;14)(p11;q32) involving the PAR1 region, which 25, 267 bases, with minus strand orientation is located in the short arm of both sex chromosomes NC_018934. CRLF2 has 3 transcripts variant; the and the immunoglobulin heavy chain locus located transcript variant 1 has 1606pb mRNA in the chromosome 14 (Figure 3). Represent the 20- NM_022148.2, this variant encodes the longer 26% of IGH translocations in B cell precursor ALL isoform NM_022148.2(Schmäh et al. 2017); the and the principal consequence is a deregulated

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transcription of CRLF2 by the physical juxtaposition sequence without mutation under transcriptional with the IGH transcriptional enhancers (Figure 4) control of IGH enhancer and the gene is (Dyer et al. 2010; Chapiro et al. 2013; Jeffries et al. overexpressed (Dyer et al. 2010). 2014; Yoda et al. 2010; Tsai et al. 2010). Detection Description The IGH/CRLF2 translocation involves the IGH/CRLF2 translocation can result of an aberrant disruption of both loci, based on this FISH technique D-J or V-DJ recombination that involves the cryptic using IGH and CRLF2 break-apart probes allows the recognition signal sequence (RSS) in the detection of the rearrangement (Figure 3). pseudoautosomal region (Figure 4). As a result, the These probes mark the centromeric region of each IGH-J or IGH-DJ regions becomes adjacent to the gene of red color and the telomeric region of green CRLF2 entire reading frame and the der(14) carries color. A normal cell with intact IGH and CRLF2 the junctions between IGH segments and the shows in each cell two close red (R) and green (G) centromeric region of CRLF2 (Dyer et al. 2010; fused (F) signals (2F); in a cell with the Chapiro et al. 2013; Yoda et al. 2010; Tsai et al. translocation, one normal F signal is conserved and 2010). one red and one green are present as a result of the The breakpoints occur approximately 8 to 16 Kb breakage (1F1R1G pattern). In abnormal upstream to the CRLF2 translation start site and, metaphases the hybridization with IGH break-apart there is a 311 bp cluster from positions 1,307,403 to probe shows a der(14) with one centromeric red 1,307,713 which contains 6 out of 19 described signal and one telomeric green signal moved to the breakpoints. Tsai et al., 2010 report that 7 of 19 derivative chromosome X or Y (Russell et al. 2009). CRLF2 breakpoints are at 5íor 3¥sides of CpG Harvey et al. 2010 reported the IGH/CRLF2 dinucleotide sequences. Similar to the IGH-BCL2 detection using a single fusion extra signal probe rearrangement, at least 18 of the 19 IGH breaks in consisting of two bacterial artificial chromosomes the IGH/CRLF2 translocation are compatible with (BAC) clones flanking CRLF2 labeled with red standard V(D)J recombination, the IGH junction is fluorochrome, and a third BAC clone centromeric to within 30bp 5¥of an RSS and this junctions contain IGH labeled with green fluorochrome. In this assay non templated nucleotide additions consistent with an IGH/CRLF2 positive cell shows the 1F2R1G the activity of terminal deoxynucleotide transferase pattern. (Dyer et al. 2010; Chapiro et al. 2013; Yoda et al. Yoda et al. 2010 amplified the IGH/CRLF2 junction 2010). on der(14) by PCR using a common IGHJ primer and Transcript spaced primers 5` of the CRLF2 coding sequence. There is no a chimeric transcript. Usually the rearrangement relocates the CRLF2 entire coding

Figure 4. The IGH/CRLF2 translocation. (A) IGH locus. The IGH breakage can occur between the variable (V-H) and diversity (D-H) regions, the orange diamonds represent the transcriptional enhancers. (B) PAR1 region. The breakage can occur 8Kb to 12Kb upstream to CRLF2. (C) The derivative chromosome 14 carries the CRLF2 juxtaposition with IGH transcriptional enhancers and (D) the derivative chromosome X or Y hold the IGH telomeric region.

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Figure 5. PATHWAY: IGH/CRLF2 rearrangement increases the expression of CRLF2. CRLF2 signaling pathway involves the activation of Jak2/STAT5 and PI3k/Akt/mTOR that are related with increase in proliferation and survival of leukemic cells. Other cellular mechanism activated by Akt is apoptosis inhibition. Additionally, CRLF2 can activate Src family members which create a feedback positive loop with Abl, and activate molecules implicated in cellular adhesion and survival (TSLP Signaling Pathway n.d.). Attarbaschi, Andishe, Maria Morak, Gunnar Cario, et al.. Fusion protein Treatment Outcome of CRLF2-Rearranged Childhood There is not a fusion protein Acute Lymphoblastic Leukaemia: A Comparative Analysis of the AIEOP-BFM and UK NCRI-CCLG Study Groups Br J Oncogenesis Haematol. 2012 Sep;158(6):772-7. doi: 10.1111/j.1365- The overexpression of CRLF2 due to the 2141.2012.09221.x. IGH/CRLF2 translocation results in its Bugarin, Cristina, Jolanda Sarno, Chiara Palmi, et al.. Fine homodimerization at cellular membrane. This leads Tuning of Surface CRLF2 Expression and Its Associated directly to constitutive activation of JAK2/STAT5, Signaling Profile in Childhood B-Cell Precursor Acute PI3k/ MTOR andSRC signaling pathway, causing Lymphoblastic Leukemia Haematologica. 2015 Jun;100(6):e229-32. doi: 10.3324/haematol.2014.114447. the leukemic blast proliferation and survival (Figures 3 and 5) (Zhong et al. 2014). Nevertheless, the IGH Chapiro, Elise, Isabelle Radford-Weiss, Hong-Anh Cung, et al.. Chromosomal Translocations Involving the IGH@ Locus translocation is not enough for the establishment of in B-Cell Precursor Acute Lymphoblastic Leukemia: 29 New the neoplastic phenotype, concurrent activation of Cases and a Review of the Literature Cancer Genet. 2013 synergistic oncogenes and loss of tumor suppressor May;206(5):162-73. doi: 10.1016/j.cancergen.2013.04.004. gene functions are necessary (Moorman et al. 2012). Dyer, Martin J. S., Takashi Akasaka, Melania Capasso, et In the near future, inhibitors for the JAK2 pathway, al.. Immunoglobulin Heavy Chain Locus Chromosomal Ruxolitinib, and for Src pathway, Dasatinib, could Translocations in B-Cell Precursor Acute Lymphoblastic be used in order to counteract oncogenic effect Leukemia: Rare Clinical Curios or Potent Genetic Drivers? Blood. 2010 Feb 25;115(8):1490-9. doi: 10.1182/blood- caused by IGH/CRLF2 in ALL patients. 2009-09-235986. Ensor, Hannah M., Claire Schwab, Lisa J. Russell, et al.. References Demographic, Clinical, and Outcome Features of Children TSLP Signaling Pathway with Acute Lymphoblastic Leukemia and CRLF2 http://www.netpath.org/netslim/TSLP_full.html, accessed Deregulation: Results from the MRC ALL97 Clinical Trial December 14, 2017.ñ257. Blood. 2011 Feb 17;117(7):2129-36. doi: 10.1182/blood- 2010-07-297135. Arber, Daniel A., Attilio Orazi, Robert Hasserjian, et al.. The 2016 Revision to the World Health Organization Harrison, Christine J.. Targeting Signaling Pathways in Classification of Myeloid Neoplasms and Acute Leukemia Acute Lymphoblastic Leukemia: New Insights Hematology Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood- Am Soc Hematol Educ Program. 2013;2013:118-25. doi: 2016-03-643544. 10.1182/asheducation-2013.1.118.

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Harvey, Richard C., Charles G. Mullighan, I.-Ming Chen, et Rochman, Yrina, Mohit Kashyap, Gertraud W. Robinson, et al.. Rearrangement of CRLF2 Is Associated with Mutation al.. Thymic Stromal Lymphopoietin-Mediated STAT5 of JAK Kinases, Alteration of IKZF1, Hispanic/Latino Phosphorylation via Kinases JAK1 and JAK2 Reveals a Key Ethnicity, and a Poor Outcome in Pediatric B-Progenitor Difference from IL-7-Induced Signaling Proc Natl Acad Sci Acute Lymphoblastic Leukemia Blood. 2010 Jul U S A. 2010 Nov 9;107(45):19455-60. doi: 1;115(26):5312-21. doi: 10.1182/blood-2009-09-245944. 10.1073/pnas.1008271107. Herold, Tobias, Stephanie Schneider, Klaus H. Metzeler, et Russell, Lisa J., Melania Capasso, Inga Vater, et al.. al. Adults with Philadelphia Chromosome-like Acute Deregulated Expression of Cytokine Receptor Gene, Lymphoblastic Leukemia Frequently Have IGH-CRLF2 and CRLF2, Is Involved in Lymphoid Transformation in B-Cell JAK2 Mutations, Persistence of Minimal Residual Disease Precursor Acute Lymphoblastic Leukemia Blood. 2009 Sep and Poor Prognosis Haematologica. 2017 Jan;102(1):130- 24;114(13):2688-98. doi: 10.1182/blood-2009-03-208397. 138. doi: 10.3324/haematol.2015.136366. Tsai, Albert G., Akinori Yoda, David M. Weinstock, and Jain, Nitin, Xinyan Lu, Naval Daver, et al.. Co-Occurrence Michael R. Lieber. t(X;14)(p22;q32)/t(Y;14)(p11;q32) of CRLF2-Rearranged and Ph+ Acute Lymphoblastic CRLF2-IGH Translocations from Human B-Lineage ALLs Leukemia: A Report of Four Patients Haematologica. 2017 Involve CpG-Type Breaks at CRLF2, but CRLF2/P2RY8 Dec;102(12):e514-e517. doi: Intrachromosomal Deletions Do Not Blood. 2010 Sep 10.3324/haematol.2016.161000. 16;116(11):1993-4. doi: 10.1182/blood-2010-05-286492. Jeffries, Sally J., Lisa Jones, Christine J. Harrison, and Lisa Yoda, Akinori, Yuka Yoda, Sabina Chiaretti, et al.. J. Russell. IGH@ Translocations Co-Exist with Other Functional Screening Identifies CRLF2 in Precursor B-Cell Primary Rearrangements in B-Cell Precursor Acute Acute Lymphoblastic Leukemia Proc Natl Acad Sci U S A. Lymphoblastic Leukemia Haematologica. 2014 2010 Jan 5;107(1):252-7. doi: 10.1073/pnas.0911726107. Aug;99(8):1334-42. doi: 10.3324/haematol.2014.103820. Zhang, W., J. Wang, Q. Wang, et al.. Identification of a Molecular Characterization of Acute Lymphoblastic Novel Type I Cytokine Receptor CRL2 Preferentially Leukemia with High CRLF2 Gene Expression in Childhood. Expressed by Human Dendritic Cells and Activated Schmh, Juliane, Birthe Fedders, Renate Panzer-Gr¸mayer, Monocytes Biochem Biophys Res Commun. 2001 Mar et al. Pediatr Blood Cancer. 2017 Oct;64(10). doi: 9;281(4):878-83. 10.1002/pbc.26539. Zhong, Jun, Jyoti Sharma, Rajesh Raju, et al.. TSLP Moorman, Anthony V., Claire Schwab, Hannah M. Ensor, et Signaling Pathway Map: A Platform for Analysis of TSLP- al.. IGH@ Translocations, CRLF2 Deregulation, and Mediated Signaling Database (Oxford). 2014 Feb Microdeletions in Adolescents and Adults with Acute 25;2014:bau007. doi: 10.1093/database/bau007. Lymphoblastic Leukemia J Clin Oncol. 2012 Sep 1;30(25):3100-8. doi: 10.1200/JCO.2011.40.3907. This article should be referenced as such: Roberts, Kathryn G., Zhaohui Gu, Debbie Payne-Turner, et Martinez-Anaya D, Juárez-Velázquez R, Moreno- al.. High Frequency and Poor Outcome of Philadelphia Lorenzana D, Pérez Vera P. t(X;14)(p22;q32) or Chromosome-Like Acute Lymphoblastic Leukemia in Adults t(Y;14)(p11;q32) IGH/CRLF2. Atlas Genet Cytogenet J Clin Oncol. 2017 Feb;35(4):394-401. doi: Oncol Haematol. 2019; 23(7):194-199. 10.1200/JCO.2016.69.0073.

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Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with telomere involvement of 20p in a case of longstanding myelodysplastic syndrome Lubomir Mitev, Liliya Grahlyova, Aselina Asenova, Verginia Uzunova, Julian Raynov Department of Cytogenetics and Molecular Biology (LM, LG, AA, VU), Clinical of Haematology (JR), Military Medical Academy, Sofia, Bulgaria, [email protected]

Published in Atlas Database: June 2017 Online updated version : http://AtlasGeneticsOncology.org/Reports/t0120q21p13MitevID100090.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70472/06-2017-t0120q21p13MitevID100090.pdf DOI: 10.4267/2042/70472 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

(multinuclearity, nuclear hyperlobulation, irregular Abstract nuclear contours and karyorrhexis). Some of the Case report on Isolated 1q21 rearrangement erythroblasts resembled the blasts of the pure der(20)t(1;20)(q21;p13) with telomere involvement erythroid leukemia (large cells with deep of 20p in a case of longstanding myelodysplastic cytoplasmic basophilia and oval nucleus with syndrome. prominent nucleolus). The test of ring sideroblasts was positive (55%). Megakaryocytic dysplasia was Clinics present with hypo- or unilobulated megakaryocytes of all sizes. Micromegakaryocyte and dysplastic Age and sex megakaryocytic fragments were also seen. 58 years old male patient. Previous history Cyto-Pathology No preleukemia; no previous malignancy; no inborn condition of note Classification Organomegaly Immunophenotype not done No hepatomegaly, no splenomegaly, no enlarged Rearranged Ig Tcr not done lymph nodes, no central nervous system Pathology involvement The peripheral blood morphology was characterized Blood with poikilo anisocytosis and presence of single oxyphilic erythroblasts. Differential blood count was WBC: 4.3X 109/l 1% myelocytes, 2% metamyelocytes, 32% bands, HB: 7.8g/dl 27% segments, 20% lymphocytes, 17% monocytes Platelets: 232X 109/l and 1% eosinophils. Blasts: 0% Electron microscopy not done Bone marrow: Bone marrow was hypercellular with Diagnosis erythroid hyperplasia (68% erythroid precursors) Refractory cytopenia with multilineage dysplasia and erythroblastic and megakaryocytic dysplasia. and ring sideroblasts. The most typical dysplastic features in the erythroid line were the changes in nuclear morphology Note

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 200 Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with Mitev L et al. telomere involvement of 20p in a case of longstanding myelodysplastic syndrome

The patient was hospitalized for the first time in Results January 2006 with two years history of mild anemia. 46,XY,der(20)t(1;20)(q21;p13)[33]. The examinations showed: Hb 104 g/dl, WBC The conventional cytogenetic study revealed 5x109/l and platelets 327x109/l. Bone marrow was karyotype of 46,XY,der(20)t(1;20)(q21;p13)[33] hypercellular with dysplasia of the erythroid lineage (Fig. 1A). presented with megaloblastic erythropoiesis. This unbalanced translocation resulted in the Conventional cytogenetic analysis revealed a formation of a derivative chromosome, composed of karyotype of 46, XY,der(20)t(1;20)(q21;p13)[20]. the recipient chromosome 20 and the additional copy The diagnosis of refractory anemia was made and the of 1q21->qter: der(20)(1qter->1q21::20p13- patient was followed-up until 2015. In this period the >20qter). In some metaphases the translocated patient was in a good clinical condition and good segment 1q21qter is as though attached to an intact quality of life maintaining hemoglobin value chromosome 20, suggesting that the breakpoint in between 95 -120 g/dl without blood transfusions. In 20p is sub-telomeric or telomeric (Fig.1A). October 2015 the patient was hospitalized again. Conventional and molecular cytogenetic analyses confirmed the karyotype of 46,XY,der(20)t(1;20)(q21;p13). The diagnosis of refractory cytopenia with multilineage dysplasia and ring sideroblasts was made and the patient received supportive treatment with blood transfusions. In February 2016 the disease progressed to a refractory anemia with excess of blasts-2 (14% myeloblasts in Figure 1. (A) Partial G- banded karyotypes demonstrating bone marrow) and one course of chemotherapy with derivative chromosome 20. (B) fluorescence 'in situ' hybridization of the derivative chromosome 20 with arm low doses of Cytarabine (80 mg daily) was carried specific probe for 1q and 20p compared with the respective out. The patient was followed-up in a satisfactory schematic model of its structure. clinical condition maintaining hemoglobin value Other molecular cytogenetics technics between 75 and 80 mg/ml and myeloblasts in the FISH examinations were carried out according to bone marrow between 2% and 4%. manufacturer's instructions, using arm specific probes for 1q (ASP1q) and 20p (ASP20p), sub- Survival telomere DNA probe for 20p (Kreatech Diagnostic, Date of diagnosis 01-2006 Leica, Germany) and telomere probe for 20p (Vysis/Abbott Molecular, Des Plaines, IL, USA). Treatment Sub-telomere DNA probe was applied Blood transfusions and chemotherapy with low independently and in combination with the arm doses of Cytarabine. specific probes for 1q. Images were captured and Complete remission: no analyzed with epifluorecsent microscope Nicon 80i Treatment related death: no (Nikon corporation, Tokyo, Japan) equipped with Relapse: no CCD camera and DAPI/red/green filter set. Status Alive Other molecular cytogenetics results Last follow up 03-2017 FISH examination with ASP1q and ASP20p probes Survival and combination of sub-telomere DNA probe with 138 In March 2017 peripheral blood showed WBC ASP for 1q showed normal sub-telomere confirmed 4.3x109/l, Hb 65 g/dl, platelets 175x109/ l and the 1q trisomy and demonstrated that the additional differential blood count 1% metamyelocytes, 5% copy of 1q21qter was translocated to the short arm bands, 52% segments, 31% lymphocytes, 6% of chromosome 20 (Fig 1B and 2A). monocytes and 5% eosinophils. Bone marrow In two of the 55 metaphases analyzed der(20) was examination revealed normocellular marrow with not present. One was with trisomy and the other one trilineage dysplasia and 4% blasts.months with tetrasomy of chromosome 1. FISH examination with both sub-telomere and telomere DNA probes Karyotype for 20p showed normal sub-telomere and telomere signal patterns - ish Sample Bone marrow der(20)t(1;20)(q21;p13)(D20S1156x2) and ish Culture time 24h der(20)t(1;20)(q21;p13)(D20S1157x2) (Fig 2B, 2C and 2D).

Banding GTG banding. Other Molecular Studies

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Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with Mitev L et al. telomere involvement of 20p in a case of longstanding myelodysplastic syndrome

Technics: one in the derivative chromosome 20 (arrowed). (E) Ideogram and microarray CGH plot of chromosome 1 Microarray examination of the patient's bone showing a gain for the segment 1q21->qter (green shaded marrow DNA was performed with CGH+SNP 60K area; the breakpoint is arrowed). (F) Ideogram and microarray platform (OGT, Oxford, UK) according microarray CGH plot of chromosome 20 showing no to the manufacturer's protocol. The hybridization of deletion on the p-arm. the reference and patient's DNA was made via incubation in Mai-Tai hybridization system Comments (SciGene, USA) for 22-hours at 65oC. Slides were Der(20)t(1;20)(q21;p13) belongs to the group of the scanned using scanner GenePix 4400A (Molecular unbalanced 1q12-21 translocations observed mostly Devices, USA) and features were extracted by as a second genetic event in a large spectrum of GenePixPro7 software (Molecular Devices, USA). hematological malignances (Zamecnikova A and Al, The microarray patient's profile was analysed with Bahar S. 2013). Unbalanced 1q12-21 translocations CytoSure Interpret software, v 4.4.6. (OGT, Oxford, affecting 20p have been reported in 10 cases: 6 with UK) using HG 19. multiple myeloma (Fiedler et al., 1992; Taniwaki et Results: al., 1994; Keung et al., 1998; Sawyer et al., 1998; aCGH study found only the gain of the segment Mohamed et al., 2007; Sawyer et al., 2014), 1 with 1q21qter and revealed no 20p losses - arr[hg] acute lymphoblastic leukemia/ lymphoblastic 1q21.1q44(142,706,628-248,514,266)x3 (Fig.3 D lymphoma (Wan et al., 2004), 1 with diffuse large B- and C). Both aCGH and FISH study with sub- cell lymphoma (Levine et al., 1985), 1 with acute telomere and telomere probes indicated that the myeloid leukemia (M7) (Yoshida et al., 2013) and 1 breakpoint in the derivative chromosome 20 is with chronic myeloproliferative disorder (L'Abbate located in the telomere region. et al., 2015). The molecular pathogenesis of der(20)t(1;20)(q12-21;p13) is linked to the gain of 1q and the losses of coding DNA from 20p. The presented case demonstrated that the breakpoint in 20p could occur in telomere region as were reported in other 1q translocations: 3 with der(2)t(1;2)(q12- 21;q37), 2 with der(16)t(1;16)(q12-21;q24) (Busson-Le Coniat M et al.,1999) and 1 with der(12)t(1;12)(q21;p13) (La Starza R et al., 1999). Because of the telomere involvement of the recipient chromosomes these 1q12-21 translocations did not result in losses of coding DNA and theirs molecular pathogenesis is possibly linked only to the gain of 1q. We supposed that in our case the missing of 20p losses as well as additional anomalies in the karyotype are the reasons for the long survival of the patient. References Fiedler W, Weh HJ, Hossfeld DK. Comparison of chromosome analysis and BCL-1 rearrangement in a series of patients with multiple myeloma. Br J Haematol. 1992 May;81(1):58-61 Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee Figure 2. (A) Metaphase fluorescence "in situ" F, Barlogie B. Jumping translocations of 1q12 in multiple hybridization with arm specific probe for 1q (green signal) myeloma: a novel mechanism for deletion of 17p in and 20p (red signal) demonstrating the translocation of the cytogenetically defined high-risk disease. Blood. 2014 Apr additional copy of 1q21qter to the short arm of chromosome 17;123(16):2504-12 20. (The derivative chromosome 20 is arrowed). (B) Fluorescence 'in situ' hybridization with arm specific probe Wan TS, Ma SK, Chow EY, Li YH, Lin SY, Chan LC. for 1q (green signal) and 20p sub-telomere probe (red Pathogenesis of jumping translocations: a molecular signal) showing two normal signals: one in the normal cytogenetics study. Leuk Res. 2004 Oct;28(10):1075-9 chromosome 20 and one fitting tightly to the additional copy Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, of 1q21qter (arrowed). (C) Metaphase fluorescence "in situ" Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, hybridization with 20p sub-telomere probe demonstrating Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, two normal signals - one in the normal and one in the Berger R. Fluorescence in situ hybridization analysis of derivative chromosome 20 (arrowed). (D) Metaphase chromosome 1 abnormalities in hematopoietic disorders: fluorescence "in situ" hybridization with 20p telomere probe demonstrating two normal signals - one in the normal and

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rearrangements of DNA satellite II and new recurrent of new nonrandom translocations in multiple myeloma with translocations. Leukemia. 1999 Dec;13(12):1975-81 multicolor spectral karyotyping. Blood. 1998 Dec 1;92(11):4269-78 Keung YK, Yung C, Wong JW, Shah F, Cobos E, Tonk V. Taniwaki M, Nishida K, Takashima T, Nakagawa H, Fujii H, Unusual presentation of multiple myeloma with "jumping Tamaki T, Shimazaki C, Horiike S, Misawa S, Abe T. translocation" involving 1q21. A case report and review of Nonrandom chromosomal rearrangements of 14q32.3 and the literature. Cancer Genet Cytogenet. 1998 Oct 19p13.3 and preferential deletion of 1p in 21 patients with 15;106(2):135-9 multiple myeloma and plasma cell leukemia. Blood. 1994 L'Abbate A, Tolomeo D, De Astis F, Lonoce A, Lo Cunsolo Oct 1;84(7):2283-90 C, Mühlematter D, Schoumans J, Vandenberghe P, Van Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato- Hoof A, Palumbo O, Carella M, Mazza T, Storlazzi CT. Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, t(15;21) translocations leading to the concurrent Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, downregulation of RUNX1 and its transcription factor Hama A, Muramatsu H, Hasegawa D, Nakamura K, partner genes SIN3A and TCF12 in myeloid disorders. Mol Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Cancer. 2015 Dec 16;14:211 Nishimura R, Izraeli S, Hayashi Y, Miyano S, Kojima S, Ito La Starza R, Stella M, Testoni N, Di Bona E, Ciolli S, E, Ogawa S. The landscape of somatic mutations in Down Marynen P, Martelli MF, Mandelli F, Mecucci C. syndrome-related myeloid disorders. Nat Genet. 2013 Characterization of 12p molecular events outside ETV6 in Nov;45(11):1293-9 complex karyotypes of acute myeloid malignancies. Br J Zamecnikova, A ; Al, Bahar S. 1q translocations Haematol. 1999 Nov;107(2):340-6 (unbalanced) in myeloid malignancies Atlas Genet Levine EG, Arthur DC, Frizzera G, Peterson BA, Hurd DD, Cytogenet Oncol Haematol. 2013;17(12):845-848. Bloomfield CD. There are differences in cytogenetic abnormalities among histologic subtypes of the non- This article should be referenced as such: Hodgkin's lymphomas. Blood. 1985 Dec;66(6):1414-22 Mitev L, Grahlyova L, Asenova A, Uzunova V, Raynov J. Mohamed AN, Bentley G, Bonnett ML, Zonder J, Al-Katib A. Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) Chromosome aberrations in a series of 120 multiple with telomere involvement of 20p in a case of myeloma cases with abnormal karyotypes. Am J Hematol. longstanding myelodysplastic syndrome. Atlas Genet 2007 Dec;82(12):1080-7 Cytogenet Oncol Haematol. 2019; 23(7):200-203. Sawyer JR, Lukacs JL, Munshi N, Desikan KR, Singhal S, Mehta J, Siegel D, Shaughnessy J, Barlogie B. Identification

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A new case of adult Acute Myeloid Leukemia with t(3;3)(p24;q26) Bo Yuan, Janice Smith, April Ewton, Sai Ravi Pingali, Arthur Zieske, Amy Breman Department of Molecular & Human Genetics, Baylor College of Medicine (BY, JS, AB), Houston, TX 77030, USA. Baylor Genetics (BY, JS, AB), Houston, TX 77030, USA, [email protected]; [email protected]. Department of Pathology Genomic Medicine, Houston Methodist Hospital (AE, AZ), Houston, TX 77030, USA. Department of Medicine, Houston Methodist Hospital (SRP), Houston, TX 77030, USA. Published in Atlas Database: November 2017 Online updated version : http://AtlasGeneticsOncology.org/Reports/t0303p24q26BremanID100091.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70473/11-2017-t0303p24q26BremanID100091.pdf DOI: 10.4267/2042/70473

secondary to refractory AML, acute Splenomegaly, Abstract fatigue, petechiae, dyspnea on exertion, neutropenic fever, refractory thrombocytopenia with hematuria Case report on a new case of adult Acute Myeloid and persistence of disease. Leukemia with t(3;3)(p24;q26). Immunophenotype Clinics CD34: positive in blasts that account for 45% of cellularity; CD61: positive in megakaryocytes. Age and sex MPO: Positive in background myeloid cells. 68 years old female patient. Negative in blasts. E-Cadherin and glycophorin: Previous history Highlights markedly decreased erythroid precursors No preleukemia; no previous malignancy; no inborn Rearranged Ig Tcr Not performed condition of note Pathology Organomegaly The marrow cellularity is approximately 90% No hepatomegaly; splenomegaly (acute (biopsy/clot); Erythroid elements: Markedly splenomegaly); no enlarged lymph nodes; no central decreased number. Normoblastic; Myeloid nervous system involvement elements: Left shifted with increased blasts. Blasts account for 18% of cells in the dilute aspirate and Blood about 45 of cells in the CD34 immunostained biopsy. Eosinophilia is seen on biopsy specimen; 9 WBC: 9.13; RBC: 2.37X 10 /l Megakaryocytes: Markedly increased in number HB: 6.7g/dl with clustering and markedly dyspoietic morphology 9 Platelets: 11X 10 /l (small hypolobulated, dysjointed nuclei, Blasts: 5% hyperlobed); Reticulin stain shows Grade 1 fibrosis. Electron microscopy Not performed Cyto-Pathology Diagnosis Classification Acute myelogenous leukemia Phenotype Survival AML with a translocation or inversion in chromosome 3; Refractory acute myelogenous Date of diagnosis 02-2017 leukemia with poor risk cytogenetics, pancytopenia Treatment

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 204 A new case of adult Acute Myeloid Leukemia with Yuan B et al. t(3;3)(p24;q26)

Reduced dose of anthracycline therapy due to cardiac function; Cytarabine and idarubicin; Dacogen; Nivolumab; Decitabine; Hydroxyurea Complete remission: no Treatment related death: no Relapse: no Status Alive

Last follow up 05-2017 Figure 2. FISH using the Cytocell EVI1 Breakapart Probe Survival 3 months demonstrating the breakpoint at 3q26.2 between EVI1 and LRRC34, a gene telomeric to EVI1, in both interphase (A) Karyotype and metaphase cells (B). Sample Bone marrow Comments Culture time 24 and 48 hours unstimulated cultures Rearrangements involving the 3q26 region have Banding GTG banding been described in up to 10% of acute myeloid Results leukemias (AML), chronic myeloid leukemias in 45,XX,t(3;3)(p24;q26),-7[20] blast crisis (CML BC), and myelodysplastic syndrome (Poppe 2006). The most common rearrangement is a paracentric inversion of the long arm, inv(3)(q21q26), although multiple rearrangements of this region have been described (Huret 2005, Jancuskova 2014, Lawce 2017). While the breakpoints are variable and may include translocations, inversions or other structural complexities, they unanimously result in EVI1 overexpression. Interphase FISH assays have been used to detect rearrangements involving the EVI1 locus at 3q26 (Wieser 2003). Monosomy 7 is also frequently present, and is associated with a poorer prognosis (Haferlach 2012, Huret 2005, Lugthart 2010). While multiple partners have been identified for EVI1, the partner of EVI1 in rearrangements Figure 1. Karyotype of the cell line demonstrating the t(3;3)(p24;q26) and loss of a copy of chromosome 7 (red involving 3p24 and 3q26 is unknown. Similar to the arrows). The lower panel shows the abnormal current case, a pericentric inversion involving both chromosomes 3 at increasing band resolution. the short and long arms of chromosome 3, Other molecular cytogenetics technics inv(3)(p24q26), has been reported in ten cases Fluorescence in situ Hybridization (FISH) (Haferlach 2012), with elevated EVI1 expression Other molecular cytogenetics results reported. Therefore, identification of the partner gene warrants further investigation. Confirmatory FISH using the Cytocell EVI1 Breakapart Probe (REF: LPH 036-A / LPH 036- A50) was performed on cells harvested from 24 hour References bone marrow culture. The FISH probe mixture Haferlach C, Bacher U, Grossmann V, Schindela S, Zenger consists of a 156 kb probe telomeric to the D3S4415 M, Kohlmann A, Kern W, Haferlach T, Schnittger S. Three marker including the LRRC34 gene (red, R), a 179 novel cytogenetically cryptic EVI1 rearrangements associated with increased EVI1 expression and poor kb probe including the entire EVI1 (MECOM) gene prognosis identified in 27 acute myeloid leukemia cases. plus flanking regions (green, G), and a 559 kb probe Genes Chromosomes Cancer. 2012 Dec;51(12):1079-85 centromeric to the EVI1 gene including the Jancuskova T, Plachy R, Zemankova L, Hardekopf DW, D3S3364 marker (aqua, A), all within the 3q26.2 Stika J, Zejskova L, Praulich I, Kreuzer KA, Rothe A, region. Interphase cells showed a 1R/1GA/1RGA Othman MA, Kosyakova N, Pekova S. Molecular signal pattern, corresponding to one split red/green characterization of the rare translocation t(3;10)(q26;q21) in an acute myeloid leukemia patient. Mol Cytogenet. signal with the aqua signal remaining with the green 2014;7:47 signal, confirming the translocation breakpoint between the EVI1 and LRRC34 genes (Figure 2). Jean-Loup Huret. 3q21q26 rearrangements in treatment However, the partner of EVI1 resulting from the related leukemia Atlas Genet Cytogenet Oncol Haematol. translocation remains unknown. 2005;9(3):234-235. 3q21q26 rearrangements in treatment related leukemia

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Lawce H, Szabo E, Torimaru Y, Davis C, Osterberg K, expressed as principal transcript in common and rare Olson S, Moore S. MECOM (EVI1) Rearrangements: A recurrent 3q26 rearrangements Genes Chromosomes Review and Case Report of Two MDS Patients with Cancer 2006 Apr;45(4):349-56 Complex 3q Inversion/Deletions J Assoc Genet Technol 2017;43(1):9-14 Wieser R, Schreiner U, Rieder H, Pirc-Danoewinata H, Grüner H, Loncarevic IF, Fonatsch C. Interphase Lugthart S, Gröschel S, Beverloo HB, Kayser S, Valk PJ, fluorescence in situ hybridization assay for the detection of van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, rearrangements of the EVI-1 locus in chromosome band van den Berg-de Ruiter E, Schanz U, Verhoef G, 3q26 in myeloid malignancies Haematologica 2003 Vandenberghe P, Ferrant A, Köhne CH, Pfreundschuh M, Jan;88(1):25-30 Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, This article should be referenced as such: Theobald M, Schlenk RF, Delwel R, Döhner K, Löwenberg B, Döhner H. Clinical, molecular, and prognostic Yuan B, Smith J, Ewton A, Pingali SR, Zieske A, Breman significance of WHO type inv(3)(q21q26 2)/t(3;3)(q21;q26 A. A new case of adult Acute Myeloid Leukemia with 2) and various other 3q abnormalities in acute myeloid t(3;3)(p24;q26). Atlas Genet Cytogenet Oncol Haematol. leukemia 2019; 23(7):204-206. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F. EVI1 is consistently

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Case Report Section t(4;11)(q23;p15) in paediatric early T cell precursor acute lymphoblastic leukemia Anurag Gupta, Sirisharani Siddaiahgari, Nagaraju Nalla, Mukkanteeswara Rao Kasaragadda, Manu Goyal Department of Hematopathology and Genetics, AMPATH, Nallagandla, Serilingampally Hyderabad, Telangana, India 500019 (AG, NN, MRK, MG); Department of Paediatric Oncology, Rainbow Children's Hospital, Karvy Lanes, Banjara Hills, Hyderabad, Telangana, India - 500 034 (SS); [email protected].

Published in Atlas Database: March 2018 Online updated version : http://AtlasGeneticsOncology.org/Reports/t0411q23p15GuptaID100094.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70474/03-2018-t0411q23p15GuptaID100094.pdf DOI: 10.4267/2042/70474 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Cyto-Pathology Case report on t(4;11)(q23;p15) in paediatric early T Classification cell precursor acute lymphoblastic leukemia. Phenotype: L1 Clinics Immunophenotype The blast cells were dim CD45 positive and Age and sex expressed moderate CD34, CD38, CD7, CD33, dim 12 years old female patient. CD2, partially CD117 and dim cytoplasmic CD3. Previous history These cells are negative for CD19, CD10, CD20, No preleukemia, no previous malignancy, no inborn HLADR, CD4, CD8, surface CD3, CD5 and CD1a. condition of note Rearranged Ig Tcr Organomegaly Not done Hepatomegaly (3 cms below right costal margin), Pathology splenomegaly (3 cms below left costal margin), Acute lymphoblastic leukemia enlarged lymph nodes (Cervical lymphadenopathy), Electron microscopy no central nervous system involvement Not done Blood Diagnosis Early T cell precursor Lymphoblastic leukemia. WBC: 1.49X 109/l HB: 6.6g/dl Survival Platelets: 1.9X 109/l Blasts: 2% Date of diagnosis Bone marrow: 30%; Hypocellular and aparticulate 12-2015 bone marrow aspirate smears and show presence of Treatment 30% blasts. High risk BFM 95

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 207 t(4;11)(q23;p15) in paediatric early T cell precursor acute Gupta A et al. lymphoblastic leukemia

Complete remission Relapse: no Comments Status Alive The t(4;11)(q23;p15) is a rare recurrent translocation Last follow up in T cell acute lymphoblastic leukemia (T cell ALL) that has been described in ten cases till date and 11-2017 leads to the fusion of NUP98 gene and RAP1GDS1 Survival gene (Mohamed AN, In press). The uniqueness of 24+months this translocation is it not involving the T cell receptor genes. It has previously been associated Karyotype with T cell lymphoblastic leukemias arising from progenitor cells aberrantly expressing myeloid Sample Bone marrow aspirate molecules (Mecucci, C. et.al., 2000). In the present Culture time 17 overnight with and without case this translocation was detected in early colcemid precursor T cell lymphoblastic leukemia (EPT- Banding GTG ALL), a recently described sub entity of T cell ALLs Results associated with inferior outcome that is characterised 46,XX,t(4?11)(q23?p15)[09]/46,XX[11] by CD1a negative, CD8 negative, CD5 weak, aberrant expression of myeloid and or stem cell Other molecular cytogenetics technics antigens like CD117 CD13 and CD33 (Coustain S. Fluorescence in situ hybridisation was done on bone et.al., 2009). Although the previous published three marrow culture pellet using NUP98 break apart case reports described aberrant myeloid antigen probe, Zytovysion, Fischai, Bremerhaven, Germany. expression, none were reported with CD117 Other molecular cytogenetics results expression. Nine cases were of adults while a single Positive for rearrangement of the NUP98 gene in case was described in 6 years old female. The 34% of the cells. translocation was detected at diagnosis in eight cases and was associated with additional abnormalities in three cases. In one case it was cytogenetically cryptic and was detected by molecular studies (Cimino G. et.al., 2001). The t(4;11) is associated with unfavourable outcome (Mohamed AN, In press). All the described cases died of the disease except a 6 years old female child who remained alive after 25 months of follow up (Pui CH. et.al., 1991). The present case was of EPTALL with t(4;11) who is alive and remains in remission 24 months post diagnosis. It is postulated that t(4;11) may impart

Figure 1: Karyogram showing t(4;11)(q23?p15) GTG unfavourable prognosis in adults rather than staining and banding method × 100 oil immersion, Carl paediatric population; however, further studies are Zeiss Axios cope and processed using IKAROS software) warranted. ACKNOWLEDGEMENTS: The authors wish to acknowledge Ms. Emily-Jane Rüschendorf and her scientific team at Zytovysion, Fischai, Bremerhaven, Germany for their support in performing FISH for NUP98 on this case. References Bloomfield CD, Goldman AI, Alimena G, Berger R, Borgström GH, Brandt L, Catovsky D, de la Chapelle A, Dewald GW, Garson OM. Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia. Blood. 1986 Feb;67(2):415-20 Figure 2: FISH using NUP98 break apart probe, Zytovysion, Fischai, Bremerhaven, Germany. Cimino G, Sprovieri T, Rapanotti MC, Foà R, Mecucci C, Mandelli F. Molecular evaluation of the NUP98/RAP1GDS1 gene frequency in adults with T-acute lymphoblastic Other Findings leukemia. Haematologica. 2001 Apr;86(4):436-7 Negative for BCR/ABL1 fusion, ETV6/RUNX1 Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, fusion, KMT2A gene rearrangement and E2A gene Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, rearrangement by FISH. Biondi A, Pui CH, Downing JR, Campana D. Early T-cell precursor leukaemia: a subtype of very high-risk acute

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lymphoblastic leukaemia. Lancet Oncol. 2009 Pui CH, Frankel LS, Carroll AJ, Raimondi SC, Shuster JJ, Feb;10(2):147-56 Head DR, Crist WM, Land VJ, Pullen DJ, Steuber CP, et al. Clinical characteristics and treatment outcome of childhood Inoue S, Tyrkus M, Ravindranath Y, Gohle N. A variant acute lymphoblastic leukemia with the t(4;11)(q21;q23): a translocation between chromosomes 4 and 11, t(4q;11p) in collaborative study of 40 cases Blood 1991 Feb a child with acute leukemia. Am J Pediatr Hematol Oncol. 1;77(3):440-7 1985 Summer;7(2):211-4 Stähli BE, Landmesser U. [Optimal Medical Therapy and Mecucci C, La Starza R, Negrini M, Sabbioni S, Crescenzi Secondary Prevention in Patients after an Acute Coronary B, Leoni P, Di Raimondo F, Krampera M, Cimino G, Tafuri Syndrome] Dtsch Med Wochenschr 2018 May;143(9):672- A, Cuneo A, Vitale A, Foà R. t(4;11)(q21;p15) translocation 679 involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia Br J This article should be referenced as such: Haematol 2000 Jun;109(4):788-93 Gupta A, Siddaiahgari S, Nalla N, Rao Kasaragadda M, Mohamed AN.. t(4;11)(q23;p15) NUP98/RAP1GDS1 Atlas Goyal M. t(4;11)(q23;p15) in paediatric early T cell Genet Cytogenet Oncol Haematol. in press precursor acute lymphoblastic leukemia. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):207-209.

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Case Report Section t(6;17)(p21;p13) and acquisition of the Philadelphia chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome Adriana Zamecnikova Kuwait Cancer Control Center, Kuwait [email protected]

Published in Atlas Database: January 2018 Online updated version : http://AtlasGeneticsOncology.org/Reports/t0617p21p13AdrianaBCRID100093.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70475/01-2018-t0617p21p13AdrianaBCRID100093.pdf DOI: 10.4267/2042/70475 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

marrow biopsy showed markedly hypercellular Abstract marrow with 69% blasts (0.4% promyelocytes, 2.7% Case report on t(6;17)(p21;p13) and acquisition of myelocytes, 1.1% neutrophils, 1.8% lymphocytes the Philadelphia chromosome translocation with and 25% erythroblasts). p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome. Cyto-Pathology Clinics Classification Phenotype Age and sex Acute myeloid leukemia without maturation 47 years old male patient. Immunophenotype Previous history Myeloid immunophenotype, (positive for CD13, Preleukemia The patient had thrombocytopenia for CD33, CD34, HLDR, CS45 and CD117) with 10 years (platelet counts ranged between 70x106/L aberrant expression of CD7. to 130x106/L, for what he had never received any treatment; no previous malignancy; no inborn Diagnosis condition of note AML with myelodysplasia-related changes. Provisional entity: AML with BCR/ABL1 Organomegaly no hepatomegaly , no splenomegaly , no enlarged lymph nodes , no central nervous system Survival involvement Date of diagnosis 08-2011 Blood Treatment WBC: 2.5X 109/l After the patient was diagnosed with MDS, therapy HB: 8.6g/dl with decitabine was administrated but the patient Platelets: 6X 109/l remained cytopenic. At progression chemotherapy Blasts: 43% combined with imatinib (400 mg/day) was Bone marrow: The bone marrow was hypocellular administrated that was escalated to 800 mg/day two with 6.5% blasts at presentation. 7 months later, the weeks later. patient MDS transformed to AML and his bone Complete remission: no

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 210 t(6;17)(p21;p13) and acquisition of the Philadelphia Zamecknikova A chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome

Status Alive Other Molecular Studies Last follow up: 04-2012 Survival Technics: 7+ The patient had traveled to his native country for Molecular studies were performed from total RNA further treatment.months extracted from the bone marrow sample using the TriZol LS reagent (Invitrogen, US) according to the Karyotype manufacturer's recommendations. cDNA was prepared from 2μg of total RNA with the Superscript Sample bone marrow II cDNA Synthesis Kit (Invitrogen, US) according to Culture time 24h manufacturer's instructions. Banding G-banding Results: Quantitative molecular studies performed with Results GeneXpert (Cepheid, US) were negative for the 47,XY,t(6;17)(p21;p13),+8 [10]/46,XY [10] at major BCR/ABL1 transcript. The absence of p210 presentation; BCR-ABL1 transcript was confirmed by reverse 47,XY,t(6;17)(p21;p13),+8,t(9;22)(q34;q11)[18]/48 transcription-polymerase chain reaction analysis; ,XY,t(6;17)(p21;p13),+8,t(9;22)(q34;q11),+10 however it showed breakpoint cluster region [2]/46,XY [20 ] at transition rearrangement between exons e1 and a2, compatible with the minor p190 BCR/ABL1 transcript. Comments We described a rare t(6;17)(p21;p13) (La Starza et al., 26) in a patient diagnosed with myelodysplastic syndrome that terminated in AML associated with acquisition of the Philadelphia chromosome translocation and the p190 BCR-ABL1 transcript. The patient initially had thrombocytopenia for 10 years, but developed MDS and at that time karyotyping revealed the chromosomal translocation t(6;17)(p21;p13) associated with an extra Figure 1. Karyotype of the patient from the time of chromosome 8. diagnosis showing the 47,XY,t(6;17)(p21;p13),+8. The initial myelodysplastic syndrome terminated to Other molecular cytogenetics technics acute myeloid leukemia, accompanied by an Fluorescence in situ hybridization studies (FISH) appearance of a new clone, characterized by a were performed on slides prepared for cytogenetic Philadelphia chromosome. Reverse transcription- analysis using a t(9;22) specific BCR/ABL dual polymerase chain reaction analysis further revealed color, dual fusion, CEP 8 and LSI P53 probes (Abott the presence of the minor p190 BCR-ABL1 Molecular/Vysis, US). transcript. Developing a Philadelphia chromosome, Other molecular cytogenetics results considered a primary anomaly, during the course of Breakpoint on 17p13 prompted us to search for MDS is extremely rare phenomenon, described only deletion of the p53 gene at presentation; however in few patients (Melo et al., 1994; Onozawa et al., fluorescence in situ hybridization with LSI p53 2003; Advani et al., 2004; Keung et al., 2004). Our probe revealed only the presence of 2 normal P53 study illustrates that the Ph translocation may signals in 500 interphase cells. Hybridization with develop from an existing MDS clone, accompanying chromosome 8 centromeric probe showed extra or perhaps inducing disease transformation. The chromosome +8 in 50 % of cells. FISH studies with availability of preleukemic MDS phase in our patient BCR/ABL performed at transition revealed 60% offers an unique opportunity to analyze the role of positive cells while retrospective studies performed BCR-ABL1 in leukemogenesis and the evolution of on stored bone marrow cells from MDS phase failed leukemia clones in hematological malignancies. to detect either the Philadelphia chromosome, either the BCR/ABL1 rearrangement.

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t(6;17)(p21;p13) and acquisition of the Philadelphia Zamecknikova A chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome

Figure 2. (A) Representative metaphase of the patient from the time of transition showing the 47,XY,t(6;17)(p21;p13),+8,t(9;22)(q34;q11) karyotype. (B) Fluorescence in situ hybridization with LSI BCR-ABL1 probe (Vysis, IL, US) showing the fusion BCR-ABL1 signal on der(9) and der(22) chromosomes. (C) Ethidium-bromide-stained agarose gel showing RT-PCR-amplified BCR-ABL1 chimaeric transcripts1. Lanes M, molecular weight marker; lane 1, e1a2 fusion in a patient; line 2, ABL internal control; line 3, e1a2-positive cell control; line 4, negative control; line 5, negative reaction with p210BCR/ABL primers in a patient; line 6, p210 CML positive control.

Melo JV, Myint H, Galton DA, Goldman JM.. P190BCR-ABL References chronic myeloid leukaemia: the missing link with chronic myelomonocytic leukaemia? Leukemia 1994 Jan;8(1):208- Advani AS. Philadelphia chromosome positive 11. myelodysplastic syndrome and acute myelogenous leukemia. Leuk Res. 2004 Jun;28(6):545-6 Onozawa M, Fukuhara T, Takahata M, Yamamoto Y, Miyake T, Maekawa I.. A case of myelodysplastic syndrome Keung YK, Beaty M, Powell BL, Molnar I, Buss D, Pettenati developed blastic crisis of chronic myelogenous leukemia M. Philadelphia chromosome positive myelodysplastic with acquisition of major BCR/ABL. Ann Hematol 2003 syndrome and acute myeloid leukemia-retrospective study Sep;82(9):593-5. and review of literature. Leuk Res. 2004 Jun;28(6):579-86 La Starza R, Aventin A, Matteucci C, Crescenzi B, Romoli This article should be referenced as such: S, Testoni N, Pierini V, Ciolli S, Sambani C, Locasciulli A, Di Zamecnikova A. t(6;17)(p21;p13) and acquisition of the Bona E, Lafage-Pochitaloff M, Martelli MF, Marynen P, Philadelphia chromosome translocation with p190 BCR- Mecucci C. Genomic gain at 6p21: a new cryptic molecular ABL1 transcript during the course of myelodysplastic rearrangement in secondary myelodysplastic syndrome and syndrome. Atlas Genet Cytogenet Oncol Haematol. acute myeloid leukemia. Leukemia. 2006 Jun;20(6):958-64 2019; 23(7):210-212.

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Case Report Section t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML Adriana Zamecnikova Kuwait Cancer Control Center, Kuwait [email protected]

Published in Atlas Database: January 2018 Online updated version : http://AtlasGeneticsOncology.org/Reports/t0617p21p13AdrianaMECOMID100092.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70476/01-2018-t0617p21p13AdrianaMECOMID100092.pdf DOI: 10.4267/2042/70476 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Case report on t(6;17)(p21;p13) associated with Cyto-Pathology t(3;3)(q21;q26.2) in AML. Classification Clinics Phenotype: Acute myeloid leukemia Age and sex Immunophenotype 25 years old female patient. Positive for CD13, CD33, CD34, HLDR, CS45, Previous history CD11b, MPO and CD64, dim expression of CD14 Preleukemia; no previous malignancy, no inborn and CD117. condition of note Diagnosis Organomegaly AML with t(3;3)(q21;q26.2) No hepatomegaly , no splenomegaly , no enlarged lymph nodes , no central nervous system Survival involvement Date of diagnosis: 12-2017 Blood Complete remission: no Last follow up: 12-2017 WBC: 20X 109/l HB: 86g/dl Karyotype Platelets: 14X 109/l Blasts: 12% Sample bone marrow Bone marrow: Hyperplastic bone marrow with Culture time 24h dyserythropoiesis, megaloblastic erythropoiesis, Banding G-banding presence of multinuclear forms, depressed megakaryocytes and 23% blasts. Results 45,XX,t(3;3)(q21;q26.2),t(6;17)(p21;p13),- 7[14]/45,XY,t(3;3)(q21;q26.2),-7[4]/ 46,XX [2]

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 213 t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML) Zamecknikova A

Figure 1. Karyotype of the patient with t(3;3)(q21;q26.2) and -7 (A) and with t(6;17)(p21;p13) as an additional anomaly (B) . Other molecular cytogenetics technics Fluorescence in situ hybridization studies (FISH) Comments were performed using Kreatechô MECOM (EVI1) We described here an AML patient with t(3;3); inv(3)(3q26) Break FISH probe and t(3;3)(q21;q26.2) associated with monosomy 7 and a SureFISH 17p13.3 (PAFAH1B1) and RUNX2 rare translocation t(6;17)(p21;p13) (La Starza et al., (6p21.1) probes. 26). The chromosomal t(6;17)(p21;p13) was found Other molecular cytogenetics results in a sideline as an additional anomaly to Hybridization with EVI1 probe confirmed the t(3;3)(q21;q26.2) and monosomy 7, therefore likely rearrangement of the gene as a result of representing a secondary aberration to these primary t(3;3)(q21;q36.2) on 10 metaphases and in 90 % of anomalies. inv(3)(q21q26.2) or t(3;3)(q21;q26.2) in interphase cells. Hybridization with Vysis D7S486/ AML or MDS result in deregulation of the proto- Vysis CEP 7 probe showed monosomy 7 in 90% of oncogene EVI1 (MECOM), which affect the cells. FISH studies with SureFISH PAFAH1B1 and RAS/receptor tyrosine kinase pathway. The RUNX2 probes showed normal signals on 2 concomitant monosomy 7 and t(6;17)(p21;p13) are metaphases without t(6;17) and juxtaposition of probably cooperating genetic lesions that developed PAFAH1B1 from 17p13.3 to 6p21.1 at the site of during malignant transformation processes in our RUNX2 gene in 5 metaphases. patient.

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t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML Zamecknikova A

Figure 2. (A) Fluorescence in situ hybridization with Kreatechô MECOM (EVI1) break apart probe confirmed the rearrangement of the gene as a result of t(3;3)(q21;q36.2). FISH studies with SureFISH PAFAH1B1 located at 17p.13.3 revealed juxtaposition of PAFAH1B1 from 17p13.3 to der(6) chromosome (B). Simultaneous hybridization with SureFISH PAFAH1B1 and RUNX2 probes showed cohybridization of PAFAH1B1 and RUNX2 genes on 6p21.1 (C).

This article should be referenced as such: References Zamecnikova A. t(6;17)(p21;p13) associated with La Starza R, Aventin A, Matteucci C, Crescenzi B, Romoli t(3;3)(q21;q26.2) in AML. Atlas Genet Cytogenet Oncol S, Testoni N, Pierini V, Ciolli S, Sambani C, Locasciulli A, Di Haematol. 2019; 23(7):213-215. Bona E, Lafage-Pochitaloff M, Martelli MF, Marynen P, Mecucci C. Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 2006 Jun;20(6):958-64

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