Vascular Endothelial Growth Factor Receptor 2

Volume 1 - Number 1 May - September 1997

Volume 20 - Number 7 July 2016 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, Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France phone +33 5 49 44 45 46 [email protected] or [email protected] .

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

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

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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 Editors Cécile Badoual and Hélène Blons (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)

Board Members Sreeparna Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Banerjee Alessandro Department of Health Sciences, University of Milan, Italy; [email protected] Beghini Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; Antonio Cuneo [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] François IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 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, Roderick Mc Leod Braunschweig, 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, Stefan Nagel Braunschweig, Germany; [email protected] Florence Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; Pedeutour [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee Susana Raimondi 38105-3678, 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] Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants Franck Viguié Malades, 75015 Paris, France; [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 20, Number 7, July 2016 Table of contents

Gene Section

PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, alpha) 380 Keli Lima, João Agostinho Machado-Neto ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa) 385 Payam Delfani, Zahra El-Schich and Anette Gjörloff Wingren KDR (kinase insert domain receptor)/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) 392 Noah Sorrelle, Rolf Brekken HMGA2 (high mobility group AT-hook 2) 403 Jian-Jun Wei NDRG1 (N-myc downstream regulated 1) 413 Maria A Nagai, Flavia R Mangone CYB5A (Cytochrome B5 Type A (microsomal)) 421 Valentina E Gomez, Amir Avan, Godefridus J Peters, Elisa Giovannetti

Leukaemia Section der(20)t(1;20)(q10-21;q11-13) 426 Adriana Zamecnikova, Soad Al Bahar t(1;19)(p13;p13.1) 429 Adriana Zamecnikova, Soad Al Bahar Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

PIP4K2A (phosphatidylinositol-5-phosphate 4- kinase, type II, alpha) Keli Lima, João Agostinho Machado-Neto Department of Clinical Pathology, School of Medical Sciences, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil (KL); Hematology and Hemotherapy Center, University of Campinas - UNICAMP, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil (JAMN); Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil (JAMN) [email protected] Published in Atlas Database: September 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/PIP4K2AID43943ch10p12.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66053/09-2015-PIP4K2AID43943ch10p12.pdf DOI: 10.4267/2042/66053

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract phosphatidylinositol signaling PIP4K2A is a lipid kinase that phosphorylates Identity phosphatidylinositol (PtdIns) 5P, generating Other names: PIPK, PI5P4KA, PIP5K2A, PtdIns4,5P2, which is an important precursor to PIP5KIIA, PIP5KII-alpha second messengers of the phosphoinositide signal transduction pathways. Recently, studies have HGNC (Hugo): PIP4K2A indicated that PIP4K2A is involved in the regulation Location: 10p12.2 of important biological processes that participate in the malignant phenotype, including cell DNA/RNA proliferation, clonogenicity and survival. The present review on PIP4K2A contains data on Description DNA/RNA, protein encoded and where the gene is The entire PIP4K2A gene is about 179.7 Kb (start: implicated. 22534837 and end: 22714574 bp; orientation: Minus Keywords: PIP4K2A; cell proliferation; strand) and contains 10 exons. clonogenicity; cell cycle; apoptosis; The PIP4K2A cDNA contains 3.8 Kb.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 380 PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, Lima K, Machado-Neto JA alpha)

phosphatidylinositol-5-phosphate 4-kinase family, Protein and major function of these proteins is to recognize the phosphatidylinositol (PtdIns) phosphorylated at Description position five (PtdIns5P) and phosphorylate inositol PIP4K2A protein consists of 406 aminoacids with a ring in position four, to generate a new lipid molecular weight of 53 kDa and has a conserved messenger, the phosphatidylinositol-4,5- phosphatidylinositol phosphate kinase (PIPK) bisphosphate (PtdIns4,5P2) (Figure 3). domain in the C-terminal region. The schematic The PtdIns4,5P2 plays an important role in representation of PIP4K2A protein is illustrated in phosphoinositide signaling, participating in several Figure 1. cell processes, including vesicle transport, cell proliferation, adhesion, apoptosis and nuclear events Expression (revised in McCrea and De Camilli, 2009). The Ubiquitous. acknowledgment about the functions of PIP4K Localisation proteins in cellular mechanism is still under construction and recent findings suggest that this PIP4K2A is predominantly located in the cytoplasm. protein family is strongly involved in oxidative However, in some cell types PIP4K2A was found in stress and cellular senescence (revised in Fiume, et both nucleus and cytoplasm (Figure 2). al., 2015). Function In contrast, the specific functions of PIP4K2A are PIP4K2A belongs to the class II of the poorly elucidated, and seems to vary according to cell type and stimulus.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 381

PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, Lima K, Machado-Neto JA alpha)

Table 1. Comparative identity of human PIP4K2A with other species (Source: http://www.ncbi.nlm.nih.gov/homologene)

For instance, PIP4K2A silencing reduces cell Somatic survival in THP1 cells (an acute myeloid leukemia Recurrent mutations in the PIP4K2A gene are rare, cells) (Jude, et al., 2015), but not in K562 cells (a 68 substitution missense, 1 substitution nonsense, 19 chronic myeloid leukemia cell line) (Peretti de substitution synonymous, 2 insertion frameshift and Albuquerque Wobeto, et al., 2014), whereas its 4 deletion frameshift mutations are reported in overexpression reduces clonogenicity and sensibility COSMIC (Catalogue of somatic mutations in cancer; to oxidative stress in O2OS cells (Jones, et al., 2013). http://cancer.sanger.ac.uk/cancergenome/projects/c PIP4K2A was initially identified in erythrocytes osmic). (Ling, et al., 1989) and its expression was found to be upregulated during erythroid differentiation (Peretti de Albuquerque Wobeto, et al., 2014, Implicated in Zaccariotto, et al., 2012), suggesting a potential Acute Leukemia participation in cell differentiation. Wobeto and colleagues (Peretti de Albuquerque Of note, among the PIP4K proteins, which include PIP4K2A, PIP4K2B and PIP4KC, PIP4K2A has Wobeto, et al., 2014) reported that PIP4K2A is a been reported as having the highest kinase activity nuclear and cytoplasm protein widely expressed in myeloid leukemia cell lines, and that PIP4K2A (Bultsma, et al., 2010). inhibition induces hemoglobin production and PIP4K2A might also form heterodimer with slightly decreases cell proliferation, but does not PIP4K2B and result in PIP4K2A nuclear modulate apoptosis in K562 cells. Using a targeted translocation (Bultsma, et al., 2010, Wang, et al., 2010). knockdown screen for phosphoinositide modulator genes as approach, Jude and colleagues (Jude, et al., Homology 2015) identified PIP4K2A as an important gene for proliferation, clonogenicity and survival of acute PIP4K2A shares high homology with the other myeloid leukemia cells. In this work, the sensibility members of the PIP4K protein family, including PIP4K2B and PIP4K2C. PIP4K2A also shares high to PIP4K2A inhibition was modulated by CDKN1A homology among different species (Table 1). (p21) and mTOR activation. Szczepanek and colleagues (Szczepanek, et al., 2012), using ex vivo drug sensitivity experiments and DNA microarray Mutations analysis in childhood acute lymphoblastic leukemia

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 382 PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, Lima K, Machado-Neto JA alpha)

cells, found that PIP4K2A gene signature was Drosophila and zebrafish, PIP4K2A orthologue associated with drug resistance for vincristine, protein knockout resulted in strong defective thioguanine, melphalan and doxorubicin. development (Gupta, et al., 2013, Elouarrat, et al., Recently, our research group (Lima, et al., 2015) 2013). In Caenorhabditis elegans, PIP4K2A observed that PIP4K2A expression was reduced in a orthologue protein knockout did not lead to panel of myeloid and lymphoid leukemia cells when developmental defects, but increased oxidative stress compared with normal leukocytes. (Fiume, et al., 2015). In mice, Pip4k2a knockout did Similar PIP4K2A expression prolife was observed in not present any aberrant phenotype (Emerling, et al., acute lymphoblastic leukemia patients compared 2013). with healthy donors. In our study, HEL cells, a myeloid leukemia cell line References that presents very low levels of p21, and Namalwa Bultsma Y, Keune WJ, Divecha N. PIP4Kbeta interacts with cells, a lymphoid leukemia cell line, that presents and modulates nuclear localization of the high-activity constitutive PI3K/AKT activation, did not show any PtdIns5P-4-kinase isoform PIP4Kalpha. Biochem J. 2010 modulation regarding cell proliferation, Sep 1;430(2):223-35 clonogenicity and apoptosis upon PIP4K2A Elouarrat D, van der Velden YU, Jones DR, Moolenaar WH, silencing (Lima, et al., 2015). Divecha N, Haramis AP. Role of phosphatidylinositol 5- phosphate 4-kinase α in zebrafish development. Int J Myelodysplastic syndromes Biochem Cell Biol. 2013 Jul;45(7):1293-301 In a cohort of 54 untreated patients with Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, myelodysplastic syndromes (MDS) was observed a Choo-Wing R, Wulf GM, Bell EL, Shim HS, Lamia KA, reduction of PIP4K2A expression in ≥5% bone Rameh LE, Bellinger G, Sasaki AT, Asara JM, Yuan X, marrow blats MDS patients group and an association Bullock A, Denicola GM, Song J, Brown V, Signoretti S, Cantley LC. Depletion of a putatively druggable class of between low expression of PIP4K2A and high blast phosphatidylinositol kinases inhibits growth of p53-null percentage. tumors. Cell. 2013 Nov 7;155(4):844-57 Interestingly, MDS patients with low levels of Fiume R, Stijf-Bultsma Y, Shah ZH, Keune WJ, Jones DR, PIP4K2A (stratified by tertiles) presented reduced Jude JG, Divecha N. PIP4K and the role of nuclear overall survival by univariate analysis (Lima, et al., phosphoinositides in tumour suppression. Biochim Biophys 2015). Acta. 2015 Jun;1851(6):898-910 Gupta A, Toscano S, Trivedi D, Jones DR, Mathre S, Clarke Breast cancer JH, Divecha N, Raghu P. Phosphatidylinositol 5-phosphate Emerling and colleagues (Emerling, et al., 2013), 4-kinase (PIP4K) regulates TOR signaling and cell growth during Drosophila development. Proc Natl Acad Sci U S A. using immunohistochemistry and western blot, 2013 Apr 9;110(15):5963-8 reported that PIP4K2A is highly expressed in primary samples and cell lines from breast cancer. In Jones DR, Foulger R, Keune WJ, Bultsma Y, Divecha N. PtdIns5P is an oxidative stress-induced second messenger this study, PIP4K2A plus PIP4K2B silencing that regulates PKB activation. FASEB J. 2013 reduced cell proliferation and tumor growth and Apr;27(4):1644-56 induced cell senescence of null, but not of p53 wild Jude JG, Spencer GJ, Huang X, Somerville TD, Jones DR, type, breast cancer cell lines. Divecha N, Somervaille TC. A targeted knockdown screen Of note that triple knockout mice for PIP4K2A, of genes coding for phosphoinositide modulators identifies PIP4K2B and TP53 presented reduced tumor burden PIP4K2A as required for acute myeloid leukemia cell proliferation and survival. Oncogene. 2015 Mar and increased tumor free survival compared with 5;34(10):1253-62 Tp53 knockout mice (Emerling, et al., 2013). Lima K, Ribeiro DM, Campos Pde M, Costa FF, Traina F, Osteosarcoma Saad ST, Sonati Mde F, Machado-Neto JA. Differential profile of PIP4K2A expression in hematological Using the osteosarcoma cell line, U2OS cells, Jones malignancies. Blood Cells Mol Dis. 2015 Oct;55(3):228-35 and colleagues (Jones, et al., 2013) observed that Ling LE, Schulz JT, Cantley LC. Characterization and induction of oxidative stress inhibits PIP4K2A purification of membrane-associated phosphatidylinositol- activity and PIP4K2A overexpression reduces 4-phosphate kinase from human red blood cells. J Biol clonogenic cell growth. Chem. 1989 Mar 25;264(9):5080-8 In contrast, PIP4K2A overexpression increased cell McCrea HJ, De Camilli P. Mutations in phosphoinositide viability in response to oxidative stress in U2OS metabolizing enzymes and human disease. Physiology cells (Jones, et al., 2013). (Bethesda). 2009 Feb;24:8-16 Peretti de Albuquerque Wobeto V, Machado-Neto JA, To be noted Zaccariotto TR, Ribeiro DM, da Silva Santos Duarte A, Saad ST, Costa FF, de Fatima Sonati M. PIPKIIα is widely PIP4K2A knockout has been reported in several expressed in hematopoietic-derived cells and may play a role in the expression of alpha- and gamma-globins in K562 organisms, including fly, worm, fish and mouse, and cells. Mol Cell Biochem. 2014 Aug;393(1-2):145-53 different phenotypes has been described. In

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 383 PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, Lima K, Machado-Neto JA alpha)

Szczepanek J, Jarzab M, Oczko-Wojciechowska M, Zaccariotto TR, Lanaro C, Albuquerque DM, Santos MN, Kowalska M, Tretyn A, Haus O, Pogorzala M, Wysocki M, Bezerra MA, Cunha FG, Lorand-Metze I, Araujo AS, Costa Jarzab B, Styczynski J. Gene expression signatures and ex FF, Sonati MF. Expression profiles of phosphatidylinositol vivo drug sensitivity profiles in children with acute phosphate kinase genes during normal human in vitro lymphoblastic leukemia. J Appl Genet. 2012 Feb;53(1):83- erythropoiesis. Genet Mol Res. 2012 Nov 12;11(4):3861-8 91 This article should be referenced as such: Wang M, Bond NJ, Letcher AJ, Richardson JP, Lilley KS, Irvine RF, Clarke JH. Genomic tagging reveals a random Lima K, Machado-Neto JA. PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, association of endogenous PtdIns5P 4-kinases IIalpha and alpha). Atlas Genet Cytogenet Oncol Haematol. 2016; IIbeta and a partial nuclear localization of the IIalpha 20(7):380-384. isoform. Biochem J. 2010 Sep 1;430(2):215-21

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 384 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Short Communication

ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa) Payam Delfani, Zahra El-Schich and Anette Gjörloff Wingren Department of Immunotechnology, Lund Institute of Technology, Lund University, Lund, Sweden (PD) Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden (ZES, AGW) [email protected]

Published in Atlas Database: September 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/ZAP70ID197ch2q11.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66054/09-2015-ZAP70ID197ch2q11.pdf DOI: 10.4267/2042/66054

Isoform 1 (full-length); Isoform 2 (1-307 is missing); Abstract Isoform 3 (1-126 is missing; 127-134 VRQTWKLE- Review on ZAP70, with data on DNA, on the protein >MRLGPRWK). encoded, and where the gene is implicated. Protein Identity Description Other names: SRK, STD, STCD, TZK, FLJ17670, ZAP70 is composed of two SH2 domains and a FLJ17679 carboxy-terminal kinase domain (Fig. 1). The crystal HGNC (Hugo): ZAP70 structure of the tandem SH2 domains of the human Location : 2q11.2 PTK ZAP70 in complex with a peptide derived from the zeta-subunit of the T-cell receptor (TCR) was DNA/RNA revealed by Hatada et al (Hatada 1995). A coiled coil of alpha-helices connects the two SH2 domains, Description producing an interface that constitutes one of the two The ZAP70 gene encodes an enzyme belonging to critical phosphotyrosine binding sites, providing the the protein tyrosine kinase (PTK) family, and it plays molecular basis for highly selective association of a role in T-cell development and lymphocyte ZAP70 with the T-cell receptor. activation. The cDNA clone encoding human The crystal structure of autoinhibited ZAP70 ZAP70 was identified for the first time by Chan et revealed a new mechanism for maintaining an al. in 1992 (Chan 1992), and mouse cDNA for both inactive kinase domain conformation (Deindl 2007), ZAP70 and Syk was cloned two years later (Ku which also have been shown in cell-based 1994). Mutations in this gene cause selective T-cell experiments (Brdicka 2005; Deindl 2009). The two defect, a severe combined immunodeficiency tandem SH2 domains that are separated by a linker (SCID) disease characterized by a selective absence region, termed interdomain A. Upon activation, of CD8-positive T-cells (review in Wang 2010). conformational changes in ZAP70 promote disassembly of the interface mediating the Transcription autoinhibited conformation, and exposure of The transcript encodes 619 amino acids with a mass tyrosines Y292, Y315 and Y319 in interdomain B, of 69,872 Da. Three isoforms have been described leading to their phosphorylation that further (http://www.uniprot.org/uniprot/P43403#structure): destabilizes the interface (Wang 2010).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 385 ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa) Delfani P, et al.

Figure 1. Schematic structure of inactive ZAP70 (adopted from Wang et al 2010). The ZAP70 domains indicated are the aminoterminal SH2 domain (N-SH2), interdomain A (I-A), carboxy-terminal SH2 domain (C-SH2), interdomain B (I-B) and the kinase domain.

Expression pathways involve many molecules, including the PTKs Src, Syk, Csk and Tec families, as well as ZAP70 protein is expressed in all major thymocyte adaptor proteins and effector enzymes in tyrosine populations, with the level of expression being phosphorylation cascades (review in Mustelin, comparable to that found in both CD4+ and CD8+ 2003). Both SH2-domains of ZAP70 are crucial for peripheral T cells (Chan 1991;Irving 1993). high avidity binding and for function in signal Stimulation of the TCR results in tyrosine transduction (Bu 1995; review by Au-Yeung 2009 phosphorylation of a number of cellular substrates. and Wang 2010). ZAP70 is phosphorylated on One of these is the TCR zeta chain, which can tyrosine residues upon TCR stimulation, and mediate the transduction of extracellular stimuli into functions in the initial step of TCR-mediated signal cellular effector functions. When ZAP70 was transduction in combination with the clustering of discovered, it represented a novel PTK and was coreceptor (CD4 or CD8)-associated LCK with T found to be expressed in T cells and natural killer cell receptors allows Lck to phosphorylate tyrosine (NK) cells. The tyrosine phosphorylation and residues in ITAMs in the intracellular tails of zeta association of ZAP70 with TCR zeta was shown to chains of the TCR-complex (Yan 2013). Doubly require the presence of src family PTKs and provide phosphorylated ITAMs in the stimulated TCR a potential mechanism by which the src family PTKs complex recruit ZAP-70 to the plasma membrane. and ZAP70 may interact to mediate TCR signal Activated ZAP70 subsequently phosphorylates at transduction (Chan 1991;Irving 1993). least two critically important adaptor proteins, linker The first indication that ZAP70 may be expressed in for the activation of T cells (LAT) and SH2-domain- the B cell lineage came from studies of B-cell containing leukocyte phosphoprotein of 76 kDa chronic lymphocytic leukemia (CLL) (Rosenwald (SLP-76 ) (Bubeck Wardenburg 1996; Zhang 1998; 2001). ZAP70 was thereafter also reported to be Au-Yeung 2009). Interdomain B in the ZAP70 expressed throughout B cell development at different molecule, between the C-terminal SH2-domain and maturational stages and that it plays a role in the the kinase domain, is also a critical region because transition of pro-B to pre-B cells in the bone marrow, of the three tyrosine residues Y292, Y315 and Y319 a checkpoint controlled by signals from the pre-B that are phosphorylated by Lck upon TCR-triggering cell receptor (pre-BCR), which monitors for (Fischer 2010). The tyrosine Y292 binds the successful rearrangement of immunoglobulin heavy ubiquitin ligase c-Cbl and control both zeta (of the chain genes (Schweighoffer 2003; Nolz 2005; TCR-CD3-zeta complex) ubiquitination and TCR Crespo 2006; Scielzo 2006). downmodulation, whereas Y315 interacts with the Localisation CT10 regulator of kinase II (CrkII ) adapter protein In the cytoplasmic compartment of the T-cell, once (Lupher 1997; Gelkop 1999; Fischer 2010). The recruited to tyrosines in the immunoreceptor tyrosine Y319 is also a binding site for PLC-gamma tyrosine-based activation motif (ITAM) of the TCR- , resulting in a positive ZAP70 kinase-mediated subunit, ZAP70 is activated by phosphorylation, at regulation through PLC-gamma phosphorylation Tyr-493 in its activation loop, by Lck (Chan 1995; and Ca2+ mobilization (Di Bartolo 1999; Williams Wange 1995). Upon phosphorylation, these bound 1999). The kinase domain itself also contains two ZAP70 molecules autophosphorylate to create tyrosine residues that are phosphorylated. docking sites for SH2-domain-containing signalling Phosphorylation of Y493 by Src-family PTKs proteins (Neumeister 1995; Katzav 1994; Couture upregulate ZAP70 activity, whereas phosphorylation 1994; Duplay 1994). Docking of ZAP70 at the of Y492 seems to do the opposite, by negatively plasma membrane is required for its activation regulate ZAP70 kinase activity (Chan 1995; Wange (reviewed in Fischer 2010). 1995). Moreover, the low molecular weight protein- tyrosine phosphatase (LMPTP) specifically Function dephosphorylates the negative regulatory Tyr-292 of Indeed, PTKs play an integral role in T cell ZAP-70, thereby counteracting inactivation of activation. TCR signal transduction and the events ZAP70 (Bottini 2002). The proteins phosphorylated leading to activation of downstream signaling by ZAP70 are not that well investigated. VHR , a

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 386 ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa) Delfani P, et al.

Vaccinia virus VH-1 related dual-specific protein rare ZAP70 mutations in humans were discovered phosphatase that inactivates the mitogen-activated before mouse models were established. The rare kinases Erk1 and Jnk, is phosphorylated at Y138 by ZAP70 mutations in humans have been described in ZAP70 (Alonso 2002). about 20 patients from different families (Arpaia The role of ZAP70 in B cells has been investigated, 1994; Elder 1994; Chan 1994b; review in Fischer but is poorly understood possibly due to the 2010 and Karaca 2013). All patients that were functional redundancy between Syk and ZAP70 reported with complete deficiency in ZAP70 activity (Fallah-Arani 2008). Studies in CLL reveal that the presented with severe clinical phenotype similar to ability of ZAP70 to enhance BCR signalling was severe combined immunodeficiency. ZAP70 independent of its kinase activity as both WT ZAP70 mutations occurring in human SCID are mostly and a catalytically inactive ZAP70 mutant induced located in the kinase domain, but mutations causing similar increases in intracellular free Ca2+ transcriptional loss of ZAP70 or destabilization of concentration upon BCR triggering (Chen 2008). the protein have also been reported. Elder et al Homology reported that a patient with a missense mutation within the highly conserved DLAARN motif of the Together with Syk, ZAP70 defines the Syk family of kinase domain (Elder 2001). Other examples are PTKs, with structural homology composed of non- described by Fischer et al and by Karaca et al myristylated cytoplasmic peptides of two N-terminal showing a lack or absence of CD8-positive T cells, Src-homology 2 (SH2) domains and a C-terminal high numbers of nonfunctional CD4-positive T cells, catalytic domain (Taniguchi 1991; Chan 1992). but normal numbers of B cells, with some patients Although Syk protein is also present in all thymocyte having normal or elevated serum immunoglobulins subsets, expression of Syk protein is down-regulated (Ig) levels and defective antibody production three- to fourfold in peripheral T cells. In contrast to (Matsuda 1999; Noraz 2000; Meinl 2000; Turul ZAP70, expression of Syk is 12- to 15-fold higher in 2009; Picard 2009; review in Fischer 2010 and peripheral B cells when compared with peripheral T Karaca 2013). cells (Chan 1994a). Both ZAP-70 and Syk are dependent upon a Src-family protein tyrosine kinase for association with the phosphorylated zeta-chain. Implicated in Thus, the differential expression of these kinases Severe combined immunodeficiency suggests the possibility of different roles for ZAP70 and Syk in TCR signaling and thymic development (SCID) (Palacios 2007). Another study showed functional Lack of ZAP70 in humans leads to a severe homology in antigen receptor signaling by immunodeficiency characterized by the absence of demonstrating that expression of ZAP70 in Syk- B CD8+ T-cells and TCR-unresponsive mature CD4+ cells reconstitutes BCR function (Kong 1995). T-cells. Mice lacking ZAP70 are also deficient in the Reconstitution required the presence of functional production of CD4+ T-cells, while the natural killer Src homology 2 (SH2) and catalytic domains of cells are unaffected (Arpaia 1994; Elder 1994; Chan ZAP70. In addition, they demonstrated that both 1994b; Negishi 1995; reviewed in Mustelin 2003). ZAP70 and Syk can bind directly to the Roifman described in 1995 a new type of selective phosphorylated Ig alpha and Ig beta subunits with T-cell deficiency characterized by persistent affinities comparable to their binding to the TCR infections reminiscent of severe combined CD3 epsilon subunit (Kong 1995). Another feature immunodeficiency (Roifman 1995). that distinguish ZAP70 from Syk is its greater The patients carry a mutation of ZAP70, resulting in dependency on Src kinases for activation and its a loss of the kinase activity. ability to phosphorylate and promote the auto- The study revealed that ZAP70 kinase appears to be activation of the downstream mitogen-activated indispensable for the development of CD8 single- protein kinase (MAPK) p38 (reviewed in Au-Yeung positive T cells as well as for the signal transduction 2009). and function of single-positive CD4 T cells. However, positive selection of CD4-positive T cells Mutations occurs in SCID patients, but the peripheral CD4-T cells do not respond normally to mitogens or to Somatic stimulation (Gelfand 1995). ZAP70 base mutation registry for ZAP70 deficiency. The result of ZAP70 mutations in humans leading to ZAP70 deficiency is a rare autosomal recessive form SCID have been described in the section above. of severe combined immunodeficiency characterized Chronic lymphocytic leukemia (CLL) by the selective absence of CD8+ T cells and by abundant CD4+ T cells in the peripheral blood that ZAP70 was first thought to be uniquely expressed in are unresponsive to TCR-mediated stimuli in vitro T-cells, thymocytes and NK-cells. However, (http://bioinf.uta.fi/ZAP70base/index.php). The first microarray analyses in CLL revealed that some B-

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 387 ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa) Delfani P, et al.

cells expressed ZAP70 (Rosenwald 2001). CLL is increased or decreased clonal growth and characterized by a clonal expansion of neoplastic downstream intracellular signaling. CD19+, CD5+, CD23+ B-cells in the blood, bone Non-Hodgkin lymphoma marrow, lymph nodes and spleen (Chiorazzi 2005). The heterogenous clinical course identifies two ZAP70 is expressed in malignant non-Hodgkin subsets of patients that includes the levels of CD38, lymphoma (NHL) B-cell subsets, including the mutational status of immunoglobulin (Ig) heavy precursor B-cell acute lymphoblastic leukemia, chain variable regions (VH) and cytogenetic diffuse large B-cell lymphoma, mantle cell abnormalities. Indeed, ZAP70 was found to be most lymphoma, multiple myeoloma, Hodgkin lymphoma discriminating gene between the two subsets of CLL, and more(Sup 2004, Admirand 2004; Wang 2005; with higher expression of ZAP70 in the unmutated Carreras 2005; Scielzo 2006). IgVH CLL group (Rosenwald 2001). Several studies B-cell acute lymphoblastic leukemia validated this finding and reported that ZAP70 (B-ALL) predicted an unfavorable disease course in terms of disease progression and overall survival (Crespo ZAP-70 was consistently expressed and 2003; Orchard 2004; Wiestner 2003; and review in phosphorylated on Tyr319 in B-lineage ALL cells Rodrïguez-Vicente 2013; Rosenquist 2013), but (Guillaume 2005). Crespo et al also found an discordant results exists (Kröber 2006). It was also expression of ZAP70 in 56% of B-ALL cases with shown that ZAP70 is a better predictor of the need pro/pre B cell phenotype (Crespo 2006), whereas for treatment than IgVH status (Rassenti 2004). childhood B-ALL showed even higher expression, in Chen et al showed early that expression of ZAP70 is nine out of twelve cases (Wandroo 2008). In adult B- associated with increased B-cell receptor signaling ALL, both less and more frequent ZAP70 expression in CLL (Chen 2002), but it seems like the presence can be detected (Wang 2005; Chakupurakal 2012). of ZAP70 in CLL is independent of its kinase Diffuse large B-cell lymphoma activity (Chen 2008), suggesting that the function is ZAP70 was expressed in a significantly higher more likely as an adaptor molecule to facilitate BCR percentage of tumor cells in the clinically more signaling in CLL, or may compete for a negative aggressive non-germinal center (GC) group regulator of Syk (review in Au-Yeung 2009). compared with the prognostically favourable GC Rassenti et al showed in 2008 that ZAP70 levels can group (Fridberg 2007). be used as an independent marker of clinical outcome in CLL (Rassenti 2008). The clinical Hodgkin lymphoma course is correlated with augmented signaling down ZAP70 is expressed in rare cases of classic Hodgkin the BCR pathway, albeit not necessarily due to its lymphoma (Sup 2004) whereas two other enzymatic actions (Gobessi 2007; review in independent studies did not detect any ZAP70- Chiorazzi 2012). It was also suggested that ZAP-70 positive cells in Hodgkin lymphoma specimens retards internalization of surface membrane IgM and (Admirand 2004; Carreras 2005). CD79b from the cell membrane, leading to Anaplastic large cell lymphoma prolonged BCR pathway signaling. An important component of ZAP-70 expression is indeed Anaplastic large cell lymphoma (ALCL) is a trafficking to solid tissue niches where signaling peripheral T cell lymphoma, often with defective through chemokine receptors and BCRs might expression of the TCR (Bonzheim 2004). Bonzheim promote survival and further proliferation (Chiorazzi et al showed that ZAP-70 was lacking in more than 2012). Many research groups are now focusing on 70% of all ALCL cases studied. Altogether, the lack the microenvironment and, for instance the role of of CD3 and ZAP70 contribute to the dysregulation chemokines, in the disease progress of CLL (review of intracellular signaling pathways controlling T cell in Burger 2014 and Ten hacken 2015). The major activation and survival. CLL compartments in humans are lymph nodes Rheumatoid arthritis (LN), bone marrow (BM) and peripheral blood (PB), B cells play an important role in the pathogenesis of which are, in different ways, giving stimuli to the rheumatoid arthritis(RA). It has been shown that neoplastic B cells. Different cell types such as ZAP70 expression in synovial fluid B cells obtained stromal cells, nurselike cells and lymphoma from RA patients was increased compared to SF B associated macrophages will interact in a complex cells of osteoarthritis patients (Tolusso 2009). cross-talk with CLL cells, together with T cells and Moreover, B cell apoptosis studied in vitro showed NK cells (Burger 2014). These cells communicate that the ZAP70- B cells spontaneously undergoing with the CLL cells through an extensive network of apoptosis were significantly higher than ZAP70+ B adhesion molecules, chemokine receptors, tumor cells. The authors concluded that the presence of necrosis factor (TNF) family members, and soluble ZAP70+ B cells increased survival and local factors (Ten hacken 2015), resulting in either inflammation in RA (Tolusso 2009).

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Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 References kd protein-tyrosine kinase that associates with the TCR zeta chain Cell 1992 Nov 13;71(4):649-62 Admirand JH, Rassidakis GZ, Abruzzo LV, Valbuena JR, Jones D, Medeiros LJ. Immunohistochemical detection of Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, ZAP-70 in 341 cases of non-Hodgkin and Hodgkin Iwashima M, Parslow TG, Weiss A. ZAP-70 deficiency in an lymphoma. Mod Pathol. 2004 Aug;17(8):954-61 autosomal recessive form of severe combined immunodeficiency Science 1994 Jun 10;264(5165):1599- Alonso A, Rahmouni S, Williams S, van Stipdonk M, 601 Jaroszewski L, Godzik A, Abraham RT, Schoenberger SP, Mustelin T. Tyrosine phosphorylation of VHR phosphatase Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, by ZAP-70. Nat Immunol. 2003 Jan;4(1):44-8 Clark EA, Weiss A. Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM. protein tyrosine kinases in TCR signaling J Immunol 1994 Defective T cell receptor signaling and CD8+ thymic May 15;152(10):4758-66 selection in humans lacking zap-70 kinase. Cell. 1994 Mar 11;76(5):947-58 Chen L, Huynh L, Apgar J, Tang L, Rassenti L, Weiss A, Kipps TJ. ZAP-70 enhances IgM signaling independent of Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, its kinase activity in chronic lymphocytic leukemia Blood Kuriyan J, Weiss A. The structure, regulation, and function 2008 Mar 1;111(5):2685-92 of ZAP-70. Immunol Rev. 2009 Mar;228(1):41-57 Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A, Bonzheim I, Geissinger E, Roth S, Zettl A, Marx A, Kipps TJ. Expression of ZAP-70 is associated with Rosenwald A, Müller-Hermelink HK, Rüdiger T. Anaplastic increased B-cell receptor signaling in chronic lymphocytic large cell lymphomas lack the expression of T-cell receptor leukemia Blood 2002 Dec 15;100(13):4609-14 molecules or molecules of proximal T-cell receptor signaling. Blood. 2004 Nov 15;104(10):3358-60 Chiorazzi N. Implications of new prognostic markers in chronic lymphocytic leukemia Hematology Am Soc Hematol Bottini N, Stefanini L, Williams S, Alonso A, Jascur T, Educ Program 2012;2012:76-87 Abraham RT, Couture C, Mustelin T. Activation of ZAP-70 through specific dephosphorylation at the inhibitory Tyr-292 Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic by the low molecular weight phosphotyrosine phosphatase leukemia N Engl J Med 2005 Feb 24;352(8):804-15 (LMPTP) J Biol Chem 2002 Jul 5;277(27):24220-4 Couture C, Baier G, Oetken C, Williams S, Telford D, Marie- Brdicka T, Kadlecek TA, Roose JP, Pastuszak AW, Weiss Cardine A, Baier-Bitterlich G, Fischer S, Burn P, Altman A, A. Intramolecular regulatory switch in ZAP-70: analogy with et al. Activation of p56lck by p72syk through physical receptor tyrosine kinases Mol Cell Biol 2005 association and N-terminal tyrosine phosphorylation Mol Jun;25(12):4924-33 Cell Biol 1994 Aug;14(8):5249-58 Bu JY, Shaw AS, Chan AC. Analysis of the interaction of Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, ZAP-70 and syk protein-tyrosine kinases with the T-cell Rozman M, Marcé S, López-Guillermo A, Campo E, antigen receptor by plasmon resonance Proc Natl Acad Sci Montserrat E. ZAP-70 expression as a surrogate for U S A 1995 May 23;92(11):5106-10 immunoglobulin-variable-region mutations in chronic lymphocytic leukemia N Engl J Med 2003 May Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, 1;348(18):1764-75 Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR. Phosphorylation of SLP-76 by the ZAP-70 Crespo M, Villamor N, Giné E, Muntañola A, Colomer D, protein-tyrosine kinase is required for T-cell receptor Marafioti T, Jones M, Camós M, Campo E, Montserrat E, function J Biol Chem 1996 Aug 16;271(33):19641-4 Bosch F. ZAP-70 expression in normal pro/pre B cells, mature B cells, and in B-cell acute lymphoblastic leukemia Burger JA, Gribben JG. The microenvironment in chronic Clin Cancer Res 2006 Feb 1;12(3 Pt 1):726-34 lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies Deindl S, Kadlecek TA, Cao X, Kuriyan J, Weiss A. Stability Semin Cancer Biol 2014 Feb;24:71-81 of an autoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response Proc Natl Carreras J, Villamor N, Colomo L, Moreno C, Ramón y Cajal Acad Sci U S A 2009 Dec 8;106(49):20699-704 S, Crespo M, Tort F, Bosch F, López-Guillermo A, Colomer D, Montserrat E, Campo E. Immunohistochemical analysis Di Bartolo V, Mège D, Germain V, Pelosi M, Dufour E, of ZAP-70 expression in B-cell lymphoid neoplasms J Michel F, Magistrelli G, Isacchi A, Acuto O. Tyrosine 319, a Pathol 2005 Mar;205(4):507-13 newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling J Biol Chem Chakupurakal G, Bell A, Griffiths M, Wandroo F, Moss P. 1999 Mar 5;274(10):6285-94 Analysis of ZAP70 expression in adult acute lymphoblastic leukaemia by real time quantitative PCR Mol Cytogenet Duplay P, Thome M, Hervé F, Acuto O. p56lck interacts via 2012 May 1;5(1):22 its src homology 2 domain with the ZAP-70 kinase J Exp Med 1994 Apr 1;179(4):1163-72 Chan AC, Dalton M, Johnson R, Kong GH, Wang T, Thoma R, Kurosaki T. Activation of ZAP-70 kinase activity by Elder ME, Skoda-Smith S, Kadlecek TA, Wang F, Wu J, phosphorylation of tyrosine 493 is required for lymphocyte Weiss A. Distinct T cell developmental consequences in antigen receptor function EMBO J 1995 Jun 1;14(11):2499- humans and mice expressing identical mutations in the 508 DLAARN motif of ZAP-70 J Immunol 2001 Jan 1;166(1):656-61 Chan AC, Irving BA, Fraser JD, Weiss A. The zeta chain is associated with a tyrosine kinase and upon T-cell antigen Fallah-Arani F, Schweighoffer E, Vanes L, Tybulewicz VL. receptor stimulation associates with ZAP-70, a 70-kDa Redundant role for Zap70 in B cell development and tyrosine phosphoprotein Proc Natl Acad Sci U S A 1991 activation Eur J Immunol 2008 Jun;38(6):1721-33 Oct 15;88(20):9166-70

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 389 ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa) Delfani P, et al.

Fischer A, Picard C, Chemin K, Dogniaux S, le Deist F, Lupher ML Jr, Songyang Z, Shoelson SE, Cantley LC, Band Hivroz C. ZAP70: a master regulator of adaptive immunity H. The Cbl phosphotyrosine-binding domain selects a Semin Immunopathol 2010 Jun;32(2):107-16 D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70 J Biol Chem Fridberg M, Servin A, Anagnostaki L, Linderoth J, Berglund 1997 Dec 26;272(52):33140-4 M, Söderberg O, Enblad G, Rosén A, Mustelin T, Jerkeman M, Persson JL, Wingren AG. Protein expression and cellular Matsuda S, Suzuki-Fujimoto T, Minowa A, Ueno H, localization in two prognostic subgroups of diffuse large B- Katamura K, Koyasu S. Temperature-sensitive ZAP70 cell lymphoma: higher expression of ZAP70 and PKC-beta mutants degrading through a proteasome-independent II in the non-germinal center group and poor survival in pathway Restoration of a kinase domain mutant by Cdc37 patients deficient in nuclear PTEN Leuk Lymphoma 2007 J Biol Chem Nov;48(11):2221-32 Meinl E, Lengenfelder D, Blank N, Pirzer R, Barata L, Hivroz Gelfand EW, Weinberg K, Mazer BD, Kadlecek TA, Weiss C. Differential requirement of ZAP-70 for CD2-mediated A. Absence of ZAP-70 prevents signaling through the activation pathways of mature human T cells J Immunol antigen receptor on peripheral blood T cells but not on 2000 Oct 1;165(7):3578-83 thymocytes J Exp Med 1995 Oct 1;182(4):1057-65 Negishi I, Motoyama N, Nakayama K, Nakayama K, Senju Gelkop S, Isakov N. T cell activation stimulates the S, Hatakeyama S, Zhang Q, Chan AC, Loh DY. Essential association of enzymatically active tyrosine-phosphorylated role for ZAP-70 in both positive and negative selection of ZAP-70 with the Crk adapter proteins J Biol Chem 1999 Jul thymocytes Nature 1995 Aug 3;376(6539):435-8 30;274(31):21519-27 Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Gobessi S, Laurenti L, Longo PG, Sica S, Leone G, Efremov Shaw AS. Binding of ZAP-70 to phosphorylated T-cell DG. ZAP-70 enhances B-cell-receptor signaling despite receptor zeta and eta enhances its autophosphorylation and absent or inefficient tyrosine kinase activation in chronic generates specific binding sites for SH2 domain-containing lymphocytic leukemia and lymphoma B cells Blood 2007 proteins Mol Cell Biol 1995 Jun;15(6):3171-8 Mar 1;109(5):2032-9 Nolz JC, Tschumper RC, Pittner BT, Darce JR, Kay NE, Guillaume N, Alleaume C, Munfus D, Capiod JC, Touati G, Jelinek DF. ZAP-70 is expressed by a subset of normal Pautard B, Desablens B, Lefrère JJ, Gouilleux F, Lassoued human B-lymphocytes displaying an activated phenotype K, Gouilleux-Gruart V. ZAP-70 tyrosine kinase is Leukemia 2005 Jun;19(6):1018-24 constitutively expressed and phosphorylated in B-lineage acute lymphoblastic leukemia cells Haematologica 2005 Noraz N, Schwarz K, Steinberg M, Dardalhon V, Jul;90(7):899-905 Rebouissou C, Hipskind R, Friedrich W, Yssel H, Bacon K, Taylor N. Alternative antigen receptor (TCR) signaling in T Hatada MH, Lu X, Laird ER, Green J, Morgenstern JP, Lou cells derived from ZAP-70-deficient patients expressing M, Marr CS, Phillips TB, Ram MK, Theriault K, et al. high levels of Syk J Biol Chem 2000 May Molecular basis for interaction of the protein tyrosine kinase 26;275(21):15832-8 ZAP-70 with the T-cell receptor Nature 1995 Sep 7;377(6544):32-8 Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia Lancet Irving BA, Chan AC, Weiss A. Functional characterization of 2004 Jan 10;363(9403):105-11 a signal transducing motif present in the T cell antigen receptor zeta chain J Exp Med 1993 Apr 1;177(4):1093-103 Palacios EH, Weiss A. Distinct roles for Syk and ZAP-70 during early thymocyte development J Exp Med 2007 Jul Karaca E, Karakoc-Aydiner E, Bayrak OF, Keles S, Sevli S, 9;204(7):1703-15 Barlan IB, Yuksel A, Chatila TA, Ozen M. Identification of a novel mutation in ZAP70 and prenatal diagnosis in a Turkish Picard C, Dogniaux S, Chemin K, Maciorowski Z, Lim A, family with severe combined immunodeficiency disorder Mazerolles F, Rieux-Laucat F, Stolzenberg MC, Debre M, Gene 2013 Jan 10;512(2):189-93 Magny JP, Le Deist F, Fischer A, Hivroz C. Hypomorphic mutation of ZAP70 in human results in a late onset Katzav S, Sutherland M, Packham G, Yi T, Weiss A. The immunodeficiency and no autoimmunity Eur J Immunol protein tyrosine kinase ZAP-70 can associate with the SH2 2009 Jul;39(7):1966-76 domain of proto-Vav J Biol Chem 1994 Dec 23;269(51):32579-85 Rassenti LZ, Jain S, Keating MJ, Wierda WG, Grever MR, Byrd JC, Kay NE, Brown JR, Gribben JG, Neuberg DS, He Kong GH, Bu JY, Kurosaki T, Shaw AS, Chan AC. F, Greaves AW, Rai KR, Kipps TJ. Relative value of ZAP- Reconstitution of Syk function by the ZAP-70 protein 70, CD38, and immunoglobulin mutation status in predicting tyrosine kinase Immunity 1995 May;2(5):485-92 aggressive disease in chronic lymphocytic leukemia Blood 2008 Sep 1;112(5):1923-30 Kröber A, Bloehdorn J, Hafner S, Bühler A, Seiler T, Kienle D, Winkler D, Bangerter M, Schlenk RF, Benner A, Lichter Rodríguez-Vicente AE, Díaz MG, et al. Chronic lymphocytic P, Döhner H, Stilgenbauer S. Additional genetic high-risk leukemia: a clinical and molecular heterogenous disease features such as 11q deletion, 17p deletion, and V3-21 Cancer Genet 2013 Mar;206(3):49-62 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia J Clin Roifman CM. A mutation in zap-70 protein tyrosine kinase Oncol 2006 Feb 20;24(6):969-75 results in a selective immunodeficiency J Clin Immunol 1995 Nov;15(6 Suppl):52S-62S Ku G, Malissen B, Mattei MG. Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans Rosenquist R, Cortese D, Bhoi S, Mansouri L, Gunnarsson Immunogenetics 1994;40(4):300-2 R. Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lundin Brockdorff J, Woetmann A, Mustelin T, Kaltoft K, Lymphoma 2013 Nov;54(11):2351-64 doi: 10 Zhang Q, Wasik MA, Röpke C, Ødum N. SHP2 regulates IL-2 induced MAPK activation, but not Stat3 or Stat5 Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, tyrosine phosphorylation, in cutaneous T cell lymphoma Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, Botstein cells Cytokine 2002 Nov 24;20(4):141-7 D, Byrd JC, Grever MR, Cheson BD, Chiorazzi N, Wilson

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 390

ZAP70 (zeta-chain (TCR) associated protein kinase 70kDa) Delfani P, et al.

WH, Kipps TJ, Brown PO, Staudt LM. Relation of gene Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu expression phenotype to immunoglobulin mutation LY, Freedman TS, Weiss A. ZAP-70: an essential kinase in genotype in B cell chronic lymphocytic leukemia J Exp Med T-cell signaling Cold Spring Harb Perspect Biol 2010 2001 Dec 3;194(11):1639-47 May;2(5):a002279 Schweighoffer E, Vanes L, Mathiot A, Nakamura T, Wang J, Young L, Win W, Taylor CR. Distribution and ZAP- Tybulewicz VL. Unexpected requirement for ZAP-70 in pre- 70 expression of WHO lymphoma categories in Shanxi, B cell development and allelic exclusion Immunity 2003 China: a review of 447 cases using a tissue microarray Apr;18(4):523-33 technique Appl Immunohistochem Mol Morphol 2005 Dec;13(4):323-32 Scielzo C, Camporeale A, Geuna M, Alessio M, Poggi A, Zocchi MR, Chilosi M, Caligaris-Cappio F, Ghia P. ZAP-70 Wange RL, Guitián R, Isakov N, Watts JD, Aebersold R, is expressed by normal and malignant human B-cell subsets Samelson LE. Activating and inhibitory mutations in of different maturational stage Leukemia 2006 adjacent tyrosines in the kinase domain of ZAP-70 J Biol Apr;20(4):689-95 Chem 1995 Aug 11;270(32):18730-3 Sup SJ, Domiati-Saad R, Kelley TW, Steinle R, Zhao X, Hsi Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, ED. ZAP-70 expression in B-cell hematologic malignancy is Henrickson SE, Zhao H, Ibbotson RE, Orchard JA, Davis not limited to CLL/SLL Am J Clin Pathol 2004 Z, Stetler-Stevenson M, Raffeld M, Arthur DC, Marti GE, Oct;122(4):582-7 Wilson WH, Hamblin TJ, Oscier DG, Staudt LM. ZAP-70 expression identifies a chronic lymphocytic leukemia Taniguchi T, Kobayashi T, Kondo J, Takahashi K, subtype with unmutated immunoglobulin genes, inferior Nakamura H, Suzuki J, Nagai K, Yamada T, Nakamura S, clinical outcome, and distinct gene expression profile Blood Yamamura H. Molecular cloning of a porcine gene syk that 2003 Jun 15;101(12):4944-51 encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis J Biol Chem 1991 Aug Williams BL, Irvin BJ, Sutor SL, Chini CC, Yacyshyn E, 25;266(24):15790-6 Bubeck Wardenburg J, Dalton M, Chan AC, Abraham RT. Phosphorylation of Tyr319 in ZAP-70 is required for T-cell Ten Hacken E, Burger JA. Microenvironment interactions antigen receptor-dependent phospholipase C-gamma1 and and B-cell receptor signaling in Chronic Lymphocytic Ras activation EMBO J 1999 Apr 1;18(7):1832-44 Leukemia: Implications for disease pathogenesis and treatment Biochim Biophys Acta 2015 Jul 17 Yan Q, Barros T, Visperas PR, Deindl S, Kadlecek TA, Weiss A, Kuriyan J. Structural basis for activation of ZAP- Tolusso B, De Santis M, Bosello S, Gremese E, Gobessi S, 70 by phosphorylation of the SH2-kinase linker Mol Cell Biol Cuoghi I, Totaro MC, Bigotti G, Rumi C, Efremov DG, 2013 Jun;33(11):2188-201 Ferraccioli G. Synovial B cells of rheumatoid arthritis express ZAP-70 which increases the survival and correlates Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, with the inflammatory and autoimmune phenotype Clin Samelson LE. LAT: the ZAP-70 tyrosine kinase substrate Immunol 2009 Apr;131(1):98-108 that links T cell receptor to cellular activation Cell 1998 Jan 9;92(1):83-92 Turul T, Tezcan I, Artac H, de Bruin-Versteeg S, Barendregt BH, Reisli I, Sanal O, van Dongen JJ, van der Burg M. This article should be referenced as such: Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency Eur J Pediatr 2009 Jan;168(1):87- Delfani P, El-Schich Z, Gjörloff Wingren A. ZAP70 (zeta- 93 chain (TCR) associated protein kinase 70kDa). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7):385-391. Wandroo F, Bell A, Darbyshire P, Pratt G, Stankovic T, Gordon J, Lawson S, Moss P. ZAP-70 is highly expressed in most cases of childhood pre-B cell acute lymphoblastic leukemia Int J Lab Hematol 2008 Apr;30(2):149-57

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KDR (kinase insert domain receptor)/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Noah Sorrelle, Rolf Brekken University of Texas Southwestern Medical Center [email protected], [email protected]

Published in Atlas Database: October 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/KDRID41055ch4q12.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66055/10-2015-KDRID41055ch4q12.pdf DOI: 10.4267/2042/66055 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

sequence. Three splice variants have been reported Abstract in Ensembl. Alternative splicing results in partial This is a concise review of the KDR/VEGFR2 gene, retention of intron 13 and an alternative stop codon, including expression, function, and implications of encoding a unique C-terminal sequence. VEGFR2 expression in cancer. Transcription factors regulating Vegfr2 expressing Keywords include ETS1 and ETS2 (Elvert G et al., 2003, Kappel A et al., 2000), EPAS1 (hypoxia inducible CD309, Kdr, Flk-1, VEGFR2, Angiogenesis, factor 2 alpha) (Elvert G et al., 2003), ETV2 Vascular Endothelial Growth Factor Receptor 2, (ER71/etsrp) (Lee D et al., 2008), and OVOL2 (Kim Tumor Angiogenesis JY et al., 2014). Identity Protein Other names: CD309, Flk1, VEGFR, VEGFR2 Description HGNC (Hugo): KDR Location: 4q12 The canonical form of VEGFR2 comprises 1356 amino acids in humans and 1345 in mice. VEGFR2 DNA/RNA is translated into a 150 kDa protein. Glycosylation of the extracellular domain results in the mature form Description at the cell surface which migrates at 230 kDa via The human KDR/VEGFR2 gene was cloned in 1991 western blot. and mapped in 1992 (Terman BI et al., 1991, Terman VEGFR2 is composed of three domains: an BI et al., 1992). The human gene (Kdr/VEGFR2) extracellular domain, transmembrane domain, and a maps to human chromosome 4. The mouse gene cytosolic domain. The extracellular domain (Kdr/Vegfr2/Flk-1) was cloned in 1991(Matthews (including N-terminus) is composed of a signal W et al., 1991). The mouse gene (Flk-1/Vegfr2) is peptide (aa: 1-20) and seven Ig-like subdomains (aa: located on mouse chromosome 5. 20-764). The second and third Ig-like subdomains (aa: 141- Transcription 207, 224-320) facilitate binding of the principal In humans, the KDR gene consists of 30 exons, VEGFR2 ligand, VEGFA (Fug G et al., 1998, spanning 47,337 bp of DNA on the reverse strand of Shinkai A et al., 1998). This is followed by a single- Chromosome 4. Exon 1 contains 5' UTR and exon pass type I transmembrane domain (aa: 765-785). 30 contains 3' UTR. All 30 exons contain translated

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The intracellular region (aa: 786-1356) consists of a Phosphorylation of the KD activation loop residues juxtamembrane domain (JMD) and kinase domain. Y1054 and Y1059 is required for kinase Biochemical analyses by Solowiej et al. (2009) activity(Kendall RL et al., 1999). determined that the JMD promotes Additional phosphorylation sites in the intracellular autophosphorylation of the kinase domain, which is domain facilitate specific interactions of between preceded by phosphorylation of the JMD residue, VEGFR2 and signaling mediators, including PLC Y801(Solowiej J et al., 2009). gamma, SHB, SCK, SHCA, GRB2, son of sevenless Replacing the VEGFR2 JMD with the VEGFR1 (SOS), and NCK. For further review, see S. Koch JMD reduces the kinase activity of VEGFR2 in vitro. and L. Claesson-Welsh, 2012, and Claesson-Welsh Conversely, replacing the VEGFR1 JMD with the and Welsh, 2013 (Claesson-Welsh L et al., 2013, VEGFR2 JMD increases the kinase activity of Koch S et al., 2012). VEGFR1(Gille H et al., 2000). Co-receptors: These data suggest that the higher kinase activity of Integrins, neuropilin-1, and CD146 promote VEGFR2 relative to VEGFR1 may be partially VEGFR2 activation, and mediate VEGFR2 explained by differences in the JMD. activities, including endothelial cell migration, The kinase domain (KD; aa: 834-1162) is split by a permeability, and angiogenesis. 70 amino acid insert (aa: 930-1000). For more information, see Table 1 and Koch and Claesson-Welsh, 2012.

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Alternative Isoforms: VEGF-D signal mostly through VEGFR3. VEGF-E In 2009, Albuquerque et al. discovered that is encoded by the Orf virus and activates VEGFR2 alternative splicing produces a soluble form of similarly to VEGF-A. Unlike VEGF-A, however, VEGFR2, present in mouse and human cornea VEGF-E is a VEGFR2-exclusive ligand. (Albuquerque RJ et al., 2009). This isoform results Expression from inclusion of the intron following exon 13 and results in a truncated product which migrates at 75 VEGFR2 is the principal VEGF receptor expressed kDa via western blot. This isoform contains only the on blood endothelial cells. Vegfr2-null mice die at extracellular domain of VEGFR2 and a unique C- E8.5 due to inadequate development of endothelial terminal sequence. Characterization of sVEGFR2 and hematopoietic cells(Shalaby F et al., 1995). revealed that it may play a role as an endogenous Vegfr2 expression levels peak during embryonic inhibitor of lymphoangiogenesis via antagonizing angiogenesis and vasculogenesis (Millauer B et al., VEGF-C/VEGFR3 signaling (Albuquerque RJ et al., 1993, Oelrichs RB et al., 1993). In adults, VEGFR2 2009). is expressed prominently on vascular endothelial Ligands: cells, where it's expression is, in part, regulated by VEGF-A (Terman BI et al., 1992), VEGF-C (Joukov fibroblast growth factor signaling(Michael S. Pepper V et al., 1996), VEGF-D (Achen MG et al., 1998), et al., 1998, Murakami M et al., 2011). Expression is and VEGF-E (M Meyer et al., 1999, Ogawa S et al., also observed on hematopoietic stem cells and 1998). VEGF-A is the primary endogenous ligand megakaryocytes(Casella I et al., 2003, Katoh O et al., activating VEGFR2 signaling, while VEGF-C and 1995, Larrivée B et al., 2003).

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Localisation small molecule receptor tyrosine kinase inhibitors (Table 4) Full length VEGFR2 is localized on the plasma membrane and is internalized in a VEGF binding- dependent manner (Koch S et al., 2012, Mutations Waltenberger J et al., 1994). Soluble VEGFR2 is secreted from the cell. Somatic Function Increased VEGFR2 copy number has been identified VEGFR2 is the premier receptor mediating VEGF- in breast(Johansson I et al., 2012), non-small cell A activity on endothelial cells, where it functions to lung cancer (Yang F et al., 2011), and neurological enhance proliferation, migration, and malignancies (Blom T et al., 2010, Puputti M et al., survival(Gerber HP et al., 1998, Jia H et al., 2004, 2006). Terman BI et al., 1992, Waltenberger J et al., 1994). Missense mutations have been identified in Vegfr2 also promotes the survival of hematopoietic hemangioma, leading to constitutive activation of stem cells(Larrivée B et al., 2003). VEGFR2 (Antonescu CR et al., 2009, Jinnin M et VEGFR2 is the principal VEGF receptor involved in al., 2008, Walter JW et al., 2002). Wang et al., 2007, vascular angiogenesis and the regulation of vascular identified that polymorphisms in the VEGFR2 were permeability(Kowanetz M et al., 2006, Terman BI et associated with coronary heart disease (Wang Y et al., 1992). VEGFR2 activity on vascular endothelial al., 2007) (Table 5). cells in tumors promotes tumor angiogenesis(K. H. Glubb et al., 2011, characterized the significance of Plate et al., 1993, Millauer B et al., 1994). For the selected single nucleotide polymorphisms on effects of VEGFR2 signaling on different cell types, VEGFR2 function and expression (Table 6). see Table 2. Of particular note, Glubb et al., 2011, identified that VEGF Signaling Inhibitors: a SNP that results in the amino acid change Q472H, Strategies employed to target VEGF signaling are which was associated with increased VEGFR2 multifocal, consisting of monoclonal antibodies for activity, and was correlated with increased both the ligands and VEGFRs, recombinant VEGFR microvessel density in non-small cell lung cancer extracellular domain fusion proteins (Table 3), and patients (Glubb DM et al., 2011) (Table 6).

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and neck (Lalla RV et al., 2003, Neuchrist C et al., Implicated in 2001), lung (Carrillo de Santa Pau E et al., 2009, Various Cancers (see Table) Chatterjee S et al., 2013, Decaussin M et al., 1999, Seto T et al., 2006, Yang F et al., 2011), melanoma The expression VEGFR2 is increased by endothelial (Straume O et al., 2003), mesothelioma (Strizzi L et cells during tumor angiogenesis (K. H. Plate et al., al., 2001), multiple myeloma (Giatromanolaki A et 1993, Millauer B et al., 1994). VEGFR2 expression al., 2010), myeloid leukemia (Padró T et al., 2002), has also been identified on myeloid-derived ovarian (Chen H et al., 2004, Spannuth WA et al., suppressor cells, where it functions in splenic MDSC 2009), pancreatic (Chung GG et al., 2006, Itakura J expansion and the chemotaxis of MDSCs into et al., 2000, von Marschall Z et al., 2000), prostate tumors (Dineen et al., 2008, Huang Y et al., 2007, (Jackson MW et al., 2002, Köllermann J et al., 2001), Roland CL et al., 2009). renal cell carcinoma (Badalian G et al., 2007), In addition to stromal cells, VEGFR2 expression by squamous (Sato H et al., 2009), and thyroid tumor cells has been identified in a variety of (Rodrèguez-Antona C et al., 2010), (Table 7). cancers, including bladder (Xia G et al., 2006), brain In some cases, tumor cell expression of VEGFR2 (Knizetova P et al., 2008, Nobusawa S1 et al., 2011, appears to play an important function in tumor Puputti M et al., 2006, Yao X et al., 2013), breast progression and correlates with worse prognosis. For (Ghosh S et al., 2008, Nakopoulou L et al., 2002, example, Yang et al. (2011) identified VEGFR2 Yan JD et al., 2015), carcinoid (Silva SR et al., copy number gains (CNG) in 32% of tumors, which 2011), cervical (Longatto-Filho A et al., 2009), was associated with increased VEGFR2 protein, colon (Giatromanolaki A et al., 2007, Takahashi Y tumor angiogenesis, and correlated with poor et al., 1995), endometrial ID: 5045> prognosis(Yang F et al., 2011). Furthermore, (Giatromanolaki A et al., 2006), esophageal (Gockel Chatterjee et al. (2013) identified that the levels of I et al., 2008), gastric (Ozdemir F et al., 2006), head VEGF/VEGFR2 binding on tumor cells strongly

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correlated with tumor angiogenesis, and selective Casella I, Feccia T, Chelucci C, Samoggia P, Castelli G, VEGFR2 inhibition had a significant combinatorial Guerriero R, Parolini I, Petrucci E, Pelosi E, Morsilli O, Gabbianelli M, Testa U, Peschle C. Autocrine-paracrine effect with MEK inhibitors in reducing tumor VEGF loops potentiate the maturation of megakaryocytic growth in preclinical models of NSCLC(Chatterjee precursors through Flt1 receptor Blood 2003 Feb S et al., 2013). 15;101(4):1316-23 Yan et al. (2015) found that VEGFR2 expression by Chatterjee S, Heukamp LC, Siobal M, Schöttle J, Wieczorek breast tumor cells was significantly correlated with C, Peifer M, Frasca D, Koker M, König K, Meder L, Rauh increased lymph node metastasis, epithelial to D, Buettner R, Wolf J, Brekken RA, Neumaier B, Christofori G, Thomas RK, Ullrich RT. Tumor VEGF:VEGFR2 mesenchymal transition (EMT) marker expression, autocrine feed-forward loop triggers angiogenesis in lung and reduced overall survival(Yan JD et al., 2015). cancer J Clin Invest 2013 Apr;123(4):1732-40 For further review of expression and function of Chen H, Ye D, Xie X, Chen B, Lu W. VEGF, VEGFRs VEGFR2 in different cancers, see Table 7 and Goel expressions and activated STATs in ovarian epithelial and Mercurio, 2013(Goel HL et al., 2013). carcinoma Gynecol Oncol 2004 Sep;94(3):630-5 Coronary Heart Disease Chung GG, Yoon HH, Zerkowski MP, Ghosh S, Thomas L, Harigopal M, Charette LA, Salem RR, Camp RL, Rimm DL, Wang et al., 2007, identified that polymorphisms in Burtness BA. Vascular endothelial growth factor, FLT-1, the VEGFR2 were associated with coronary heart and FLK-1 analysis in a pancreatic cancer tissue microarray disease (Wang Y et al., 2007) (Table 5). Cancer 2006 Apr 15;106(8):1677-84 Hemangioma Claesson-Welsh L, Welsh M. VEGFA and tumour angiogenesis J Intern Med 2013 Feb;273(2):114-27 Missense mutations have been identified in hemangioma, leading to constitutive activation of Decaussin M, Sartelet H, Robert C, Moro D, Claraz C, Brambilla C, Brambilla E. Expression of vascular endothelial VEGFR2 (Antonescu CR et al., 2009, Jinnin M et growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 al., 2008, Walter JW et al., 2002). and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival J References Pathol 1999 Aug;188(4):369-77 Dineen SP, Lynn KD, Holloway SE, Miller AF, Sullivan JP, Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks Shames DS, Beck AW, Barnett CC, Fleming JB, Brekken AF, Alitalo K, Stacker SA. Vascular endothelial growth factor RA. Vascular endothelial growth factor receptor 2 mediates D (VEGF-D) is a ligand for the tyrosine kinases VEGF macrophage infiltration into orthotopic pancreatic tumors in receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl mice Cancer Res 2008 Jun 1;68(11):4340-6 Acad Sci U S A. 1998 Jan 20;95(2):548-53 Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi Acker T, Rauter M, Plate K, Sieweke M, Breier G, Flamme S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, I. Cooperative interaction of hypoxia-inducible factor-2alpha Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, (HIF-2alpha ) and Ets-1 in the transcriptional activation of Mizuki N, Alexander JS, Peterson ML, Brekken RA, vascular endothelial growth factor receptor-2 (Flk-1) J Biol Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J. Chem 2003 Feb 28;278(9):7520-30 Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic Fuh G, Li B, Crowley C, Cunningham B, Wells JA. vessel growth Nat Med 2009 Sep;15(9):1023-30 Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor J Biol Antonescu CR, Yoshida A, Guo T, Chang NE, Zhang L, Chem 1998 May 1;273(18):11197-204 Agaram NP, Qin LX, Brennan MF, Singer S, Maki RG. KDR activating mutations in human angiosarcomas are sensitive Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit to specific kinase inhibitors Cancer Res 2009 Sep V, Ferrara N. Vascular endothelial growth factor regulates 15;69(18):7175-9 endothelial cell survival through the phosphatidylinositol 3'- kinase/Akt signal transduction pathway Requirement for Badalian G, Derecskei K, Szendroi A, Szendroi M, Tímá J. Flk-1/KDR activation J Biol Chem EGFR and VEGFR2 protein expressions in bone metastases of clear cell renal cancer Anticancer Res 2007 Ghosh S, Sullivan CA, Zerkowski MP, Molinaro AM, Rimm Mar-Apr;27(2):889-94 DL, Camp RL, Chung GG. High levels of vascular endothelial growth factor and its receptors (VEGFR-1, Blom T, Roselli A, Häyry V, Tynninen O, Wartiovaara K, VEGFR-2, neuropilin-1) are associated with worse outcome Korja M, Nordfors K, Haapasalo H, Nupponen NN. in breast cancer Hum Pathol 2008 Dec;39(12):1835-43 Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive Giatromanolaki A, Bai M, Margaritis D, Bourantas KL, neuroectodermal tumors J Neurooncol 2010 Apr;97(2):217- Koukourakis MI, Sivridis E, Gatter KC. Hypoxia and 24 activated VEGF/receptor pathway in multiple myeloma Anticancer Res 2010 Jul;30(7):2831-6 Carrillo de Santa Pau E, Arias FC, Caso Peláez E, Muñoz Molina GM, Sánchez Hernández I, Muguruza Trueba I, Gille H, Kowalski J, Yu L, Chen H, Pisabarro MT, Davis- Moreno Balsalobre R, Sacristán López S, Gómez Pinillos A, Smyth T, Ferrara N. A repressor sequence in the del Val Toledo Lobo M. Prognostic significance of the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively expression of vascular endothelial growth factors A, B, C, inhibits vascular endothelial growth factor-dependent and D and their receptors R1, R2, and R3 in patients with phosphatidylinositol 3'-kinase activation and endothelial nonsmall cell lung cancer Cancer 2009 Apr 15;115(8):1701-12 cell migration EMBO J 2000 Aug 1;19(15):4064-73

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Glubb DM, Cerri E, Giese A, Zhang W, Mirza O, Thompson effect of VEGF on apoptotic cell death caused by ionizing EE, Chen P, Das S, Jassem J, Rzyman W, Lingen MW, radiation Cancer Res 1995 Dec 1;55(23):5687-92 Salgia R, Hirsch FR, Dziadziuszko R, Ballmer-Hofer K, Innocenti F. Novel functional germline variants in the VEGF Kendall RL, Rutledge RZ, Mao X, Tebben AJ, Hungate RW, receptor 2 gene and their effect on gene expression and Thomas KA. Vascular endothelial growth factor receptor microvessel density in lung cancer Clin Cancer Res 2011 KDR tyrosine kinase activity is increased by Aug 15;17(16):5257-67 autophosphorylation of two activation loop tyrosine residues J Biol Chem 1999 Mar 5;274(10):6453-60 Gockel I, Moehler M, Frerichs K, Drescher D, Trinh TT, Duenschede F, Borschitz T, Schimanski K, Biesterfeld S, Kim JY, Lee RH, Kim TM, Kim DW, Jeon YJ, Huh SH, Oh Herzer K, Galle PR, Lang H, Junginger T, Schimanski CC. SY, Kyba M, Kataoka H, Choi K, Ornitz DM, Chae JI, Park Co-expression of receptor tyrosine kinases in esophageal C. OVOL2 is a critical regulator of ER71/ETV2 in generating adenocarcinoma and squamous cell cancer Oncol Rep FLK1+, hematopoietic, and endothelial cells from embryonic 2008 Oct;20(4):845-50 stem cells Blood 2014 Nov 6;124(19):2948-52 Goel HL, Mercurio AM. VEGF targets the tumour cell Nat Knizetova P, Ehrmann J, Hlobilkova A, Vancova I, Kalita O, Rev Cancer 2013 Dec;13(12):871-82 Kolar Z, Bartek J. Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the Hervé MA, Meduri G, Petit FG, Domet TS, Lazennec G, VEGF-VEGFR2 (KDR) interplay Cell Cycle 2008 Aug Mourah S, Perrot-Applanat M. Regulation of the vascular 15;7(16):2553-61 endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus J Endocrinol 2006 Koch S, Claesson-Welsh L. Signal transduction by vascular Jan;188(1):91-9 endothelial growth factor receptors Cold Spring Harb Perspect Med 2012 Jul;2(7):a006502 Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, Carbone DP. Distinct roles of VEGFR-1 and Kowanetz M, Ferrara N. Vascular endothelial growth factor VEGFR-2 in the aberrant hematopoiesis associated with signaling pathways: therapeutic perspective Clin Cancer elevated levels of VEGF Blood 2007 Jul 15;110(2):624-31 Res 2006 Sep 1;12(17):5018-22 Itakura J, Ishiwata T, Shen B, Kornmann M, Korc M. Lalla RV, Boisoneau DS, Spiro JD, Kreutzer DL. Expression Concomitant over-expression of vascular endothelial of vascular endothelial growth factor receptors on tumor growth factor and its receptors in pancreatic cancer Int J cells in head and neck squamous cell carcinoma Arch Cancer 2000 Jan 1;85(1):27-34 Otolaryngol Head Neck Surg 2003 Aug;129(8):882-8 Jackson MW, Roberts JS, Heckford SE, Ricciardelli C, Stahl Larrivée B, Lane DR, Pollet I, Olive PL, Humphries RK, J, Choong C, Horsfall DJ, Tilley WD. A potential autocrine Karsan A. Vascular endothelial growth factor receptor-2 role for vascular endothelial growth factor in prostate cancer induces survival of hematopoietic progenitor cells J Biol Cancer Res 2002 Feb 1;62(3):854-9 Chem 2003 Jun 13;278(24):22006-13 Jia H, Bagherzadeh A, Bicknell R, Duchen MR, Liu D, Lee D, Park C, Lee H, Lugus JJ, Kim SH, Arentson E, Zachary I. Vascular endothelial growth factor (VEGF)-D and Chung YS, Gomez G, Kyba M, Lin S, Janknecht R, Lim DS, VEGF-A differentially regulate KDR-mediated signaling and Choi K. ER71 acts downstream of BMP, Notch, and Wnt biological function in vascular endothelial cells J Biol Chem signaling in blood and vessel progenitor specification Cell 2004 Aug 20;279(34):36148-57 Stem Cell 2008 May 8;2(5):497-507 Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, Longatto-Filho A, Pinheiro C, Martinho O, Moreira MA, Bischoff J, Vikkula M, Boye E, Olsen BR. Suppressed Ribeiro LF, Queiroz GS, Schmitt FC, Baltazar F, Reis RM. NFAT-dependent VEGFR1 expression and constitutive Molecular characterization of EGFR, PDGFRA and VEGFR2 signaling in infantile hemangioma Nat Med 2008 VEGFR2 in cervical adenosquamous carcinoma BMC Nov;14(11):1236-46 Cancer 2009 Jun 29;9:212 Johansson I, Aaltonen KE, Ebbesson A, Grabau D, Wigerup Matthews W, Jordan CT, Gavin M, Jenkins NA, Copeland C, Hedenfalk I, Rydén L. Increased gene copy number of NG, Lemischka IR. A receptor tyrosine kinase cDNA KIT and VEGFR2 at 4q12 in primary breast cancer is isolated from a population of enriched primitive related to an aggressive phenotype and impaired prognosis hematopoietic cells and exhibiting close genetic linkage to Genes Chromosomes Cancer 2012 Apr;51(4):375-83 c-kit Proc Natl Acad Sci U S A 1991 Oct 15;88(20):9026-30 Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Meyer M, Clauss M, Lepple-Wienhues A, Waltenberger J, Kukk E, Saksela O, Kalkkinen N, Alitalo K. A novel vascular Augustin HG, Ziche M, Lanz C, Büttner M, Rziha HJ, Dehio endothelial growth factor, VEGF-C, is a ligand for the Flt4 C. A novel vascular endothelial growth factor encoded by (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases Orf virus, VEGF-E, mediates angiogenesis via signalling EMBO J 1996 Jan 15;15(2):290-98 through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases EMBO J 1999 Jan 15;18(2):363-74 Köllermann J, Helpap B. Expression of vascular endothelial growth factor (VEGF) and VEGF receptor Flk-1 in benign, Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A. premalignant, and malignant prostate tissue Am J Clin Glioblastoma growth inhibited in vivo by a dominant- Pathol 2001 Jul;116(1):115-21 negative Flk-1 mutant Nature 1994 Feb 10;367(6463):576- 9 Kappel A, Schlaeger TM, Flamme I, Orkin SH, Risau W, Breier G. Role of SCL/Tal-1, GATA, and ets transcription Murakami M, Nguyen LT, Hatanaka K, Schachterle W, factor binding sites for the regulation of flk-1 expression Chen PY, Zhuang ZW, Black BL, Simons M. FGF- during murine vascular development Blood 2000 Nov dependent regulation of VEGF receptor 2 expression in 1;96(9):3078-85 mice J Clin Invest 2011 Jul;121(7):2668-78 Katoh O, Tauchi H, Kawaishi K, Kimura A, Satow Y. Nakopoulou L, Stefanaki K, Panayotopoulou E, Expression of the vascular endothelial growth factor (VEGF) Giannopoulou I, Athanassiadou P, Gakiopoulou-Givalou H, receptor gene, KDR, in hematopoietic cells and inhibitory Louvrou A. Expression of the vascular endothelial growth

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factor receptor-2/Flk-1 in breast carcinomas: correlation formation and vasculogenesis in Flk-1-deficient mice Nature with proliferation Hum Pathol 2002 Sep;33(9):863-70 1995 Jul 6;376(6535):62-6 Neuchrist C, Erovic BM, Handisurya A, Steiner GE, Shinkai A, Ito M, Anazawa H, Yamaguchi S, Shitara K, Rockwell P, Gedlicka C, Burian M. Vascular endothelial Shibuya M. Mapping of the sites involved in ligand growth factor receptor 2 (VEGFR2) expression in squamous association and dissociation at the extracellular domain of cell carcinomas of the head and neck Laryngoscope 2001 the kinase insert domain-containing receptor for vascular Oct;111(10):1834-41 endothelial growth factor J Biol Chem 1998 Nov 20;273(47):31283-8 Nobusawa S, Stawski R, Kim YH, Nakazato Y, Ohgaki H. Amplification of the PDGFRA, KIT and KDR genes in Silva SR, Bowen KA, Rychahou PG, Jackson LN, Weiss HL, glioblastoma: a population-based study Neuropathology Lee EY, Townsend CM Jr, Evers BM. VEGFR-2 expression 2011 Dec;31(6):583-8 in carcinoid cancer cells and its role in tumor growth and metastasis Int J Cancer 2011 Mar 1;128(5):1045-56 Oelrichs RB, Reid HH, Bernard O, Ziemiecki A, Wilks AF. NYK/FLK-1: a putative receptor protein tyrosine kinase Solowiej J, Bergqvist S, McTigue MA, Marrone T, Quenzer isolated from E10 embryonic neuroepithelium is expressed T, Cobbs M, Ryan K, Kania RS, Diehl W, Murray BW. in endothelial cells of the developing embryo Oncogene Characterizing the effects of the juxtamembrane domain on 1993 Jan;8(1):11-8 vascular endothelial growth factor receptor-2 enzymatic activity, autophosphorylation, and inhibition by axitinib Ogawa S, Oku A, Sawano A, Yamaguchi S, Yazaki Y, Biochemistry 2009 Jul 28;48(29):7019-31 Shibuya M. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes Spannuth WA, Nick AM, Jennings NB, Armaiz-Pena GN, KDR/Flk-1 receptor and carries a potent mitotic activity Mangala LS, Danes CG, Lin YG, Merritt WM, Thaker PH, without heparin-binding domain J Biol Chem 1998 Nov Kamat AA, Han LY, Tonra JR, Coleman RL, Ellis LM, Sood 20;273(47):31273-82 AK. Functional significance of VEGFR-2 on ovarian cancer cells Int J Cancer 2009 Mar 1;124(5):1045-53 Ozdemir F, Akdogan R, Aydin F, Reis A, Kavgaci H, Gul S, Akdogan E. The effects of VEGF and VEGFR-2 on survival Straume O, Akslen LA. Increased expression of VEGF- in patients with gastric cancer J Exp Clin Cancer Res 2006 receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is Mar;25(1):83-8 associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma Padró T, Bieker R, Ruiz S, Steins M, Retzlaff S, Bürger H, Angiogenesis 2003;6(4):295-301 Büchner T, Kessler T, Herrera F, Kienast J, Müller-Tidow C, Serve H, Berdel WE, Mesters RM. Overexpression of Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, vascular endothelial growth factor (VEGF) and its cellular Tassi G, Puntoni R, Mutti L, Procopio A. Vascular receptor KDR (VEGFR-2) in the bone marrow of patients endothelial growth factor is an autocrine growth factor in with acute myeloid leukemia Leukemia 2002 human malignant mesothelioma J Pathol 2001 Jul;16(7):1302-10 Apr;193(4):468-75 Plate KH, Breier G, Millauer B, Ullrich A, Risau W. Up- Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. regulation of vascular endothelial growth factor and its Expression of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor receptor, KDR, correlates with vascularity, metastasis, and angiogenesis Cancer Res 1993 Dec 1;53(23):5822-7 proliferation of human colon cancer Cancer Res 1995 Sep 15;55(18):3964-8 Puputti M, Tynninen O, Sihto H, Blom T, Mäenpæ H, Isola J, Paetau A, Joensuu H, Nupponen NN. Amplification of Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy KIT, PDGFRA, VEGFR2, and EGFR in gliomas Mol Cancer RL, Shows TB. Identification of a new endothelial cell Res 2006 Dec;4(12):927-34 growth factor receptor tyrosine kinase Oncogene 1991 Sep;6(9):1677-83 Rodríguez-Antona C, Pallares J, Montero-Conde C, Inglada-Pérez L, Castelblanco E, Landa I, Leskelä S, Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Leandro-García LJ, López-Jiménez E, Letón R, Cascón A, Armellino DC, Gospodarowicz D, Böhlen P. Identification of Lerma E, Martin MC, Carralero MC, Mauricio D, Cigudosa the KDR tyrosine kinase as a receptor for vascular JC, Matias-Guiu X, Robledo M. Overexpression and endothelial cell growth factor Biochem Biophys Res activation of EGFR and VEGFR2 in medullary thyroid Commun 1992 Sep 30;187(3):1579-86 carcinomas is related to metastasis Endocr Relat Cancer 2010 Jan 29;17(1):7-16 Terman BI, Jani-Sait S, Carrion ME, Shows TB. The KDR gene maps to human chromosome 4q31 2----q32, a locus Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT, which is distinct from locations for other type III growth factor Sadegh L, Sullivan JP, Shames DS, Brekken RA. Inhibition receptor tyrosine kinases Cytogenet Cell Genet of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya cancer xenografts Mol Cancer Ther 2009 Jul;8(7):1761-71 M, Heldin CH. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth Sato H, Takeda Y. VEGFR2 expression and relationship factor J Biol Chem 1994 Oct 28;269(43):26988-95 between tumor neovascularization and histologic characteristics in oral squamous cell carcinoma J Oral Sci Walter JW, North PE, Waner M, Mizeracki A, Blei F, Walker 2009 Dec;51(4):551-7 JW, Reinisch JF, Marchuk DA. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma Seto T, Higashiyama M, Funai H, Imamura F, Uematsu K, Genes Chromosomes Cancer 2002 Mar;33(3):295-303 Seki N, Eguchi K, Yamanaka T, Ichinose Y. Prognostic value of expression of vascular endothelial growth factor Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, and its flt-1 and KDR receptors in stage I non-small-cell lung Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are cancer Lung Cancer 2006 Jul;53(1):91-6 associated with coronary heart disease J Am Coll Cardiol 2007 Aug 21;50(8):760-7 Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood-island

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KDR (kinase insert domain receptor)/Vascular Endothelial Sorrelle N, Brekken R Growth Factor Receptor 2 (VEGFR2)

Xia G, Kumar SR, Hawes D, Cai J, Hassanieh L, Groshen Yao X, Ping Y, Liu Y, Chen K, Yoshimura T, Liu M, Gong S, Zhu S, Masood R, Quinn DI, Broek D, Stein JP, Gill PS. W, Chen C, Niu Q, Guo D, Zhang X, Wang JM, Bian X. Expression and significance of vascular endothelial growth Vascular endothelial growth factor receptor 2 (VEGFR-2) factor receptor 2 in bladder cancer J Urol 2006 plays a key role in vasculogenic mimicry formation, Apr;175(4):1245-52 neovascularization and tumor initiation by Glioma stem-like cells PLoS One 2013;8(3):e57188 Yan JD, Liu Y, Zhang ZY, Liu GY, Xu JH, Liu LY, Hu YM. Expression and prognostic significance of VEGFR-2 in von Marschall Z, Cramer T, Höcker M, Burde R, Plath T, breast cancer Pathol Res Pract 2015 Jul;211(7):539-43 Schirner M, Heidenreich R, Breier G, Riecken EO, Wiedenmann B, Rosewicz S. De novo expression of Yang F, Tang X, Riquelme E, Behrens C, Nilsson MB, Giri vascular endothelial growth factor in human pancreatic U, Varella-Garcia M, Byers LA, Lin HY, Wang J, Raso MG, cancer: evidence for an autocrine mitogenic loop Girard L, Coombes K, Lee JJ, Herbst RS, Minna JD, Gastroenterology 2000 Nov;119(5):1358-72 Heymach JV, Wistuba II. Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in This article should be referenced as such: patients with non-small-cell lung carcinoma who receive Sorrelle N, Brekken R. KDR (kinase insert domain adjuvant chemotherapy Cancer Res 2011 Aug receptor)/Vascular Endothelial Growth Factor Receptor 15;71(16):5512-21 2 (VEGFR2). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7):392-402.

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OPEN ACCESS JOURNAL INIST-CNRS

Gene Section Review

HMGA2 (high mobility group AT-hook 2) Jian-Jun Wei Floyd Elroy Patterson Research Professor of Pathology, Department of Pathology and Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Women's Health Research Institute, 251 East Huron Street, Feinberg 7-334, Chicago, Illinois 60611; [email protected]

Published in Atlas Database: October 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/HMGICID82.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66056/10-2015-HMGICID82.pdf DOI: 10.4267/2042/66056 This article is an update of : Broberg K. HMGA2 (high mobility group AT-hook 2). Atlas Genet Cytogenet Oncol Haematol 2006;10(3) Pedeutour F. HMGIC (High mobility group protein isoform I-C). Atlas Genet Cytogenet Oncol Haematol 2000;4(2)

Keywords Abstract HMGA2, Development, miRNA regulation, Stem HMGA2, the High Mobility Group A2 gene, is a cell self-renewal, transcription regulation, Oncofetal non-histone and architectural transcription factor. As protein, neoplasia, Aging and senescence, epithelial- an oncofetal protein, HMGA2 plays an important to-mesenchymal transition (EMT), non-random role in development and contributes to the chromosomal translocation. tumorigenesis of many epithelial and mesenchymal tumors. Identity Upregulation of HMGA2 by non-random Other names: HMGIC, BABL, LIPO, STQTL9 chromosomal translocations is common in HGNC (Hugo): HMGA2 mesenchymal tumors, whereas by the altered transcription regulation is likely the major Location: 12q14.3 mechanism in malignant epithelial tumors and it Local order involves much more complex mechanisms. HMGA2 telomeric to CDK4, centromeric to MDM2 directly and indirectly regulates the multiple biological and oncogenic pathways. Its oncogenic property remains to be fully characterized.

FISH Probe(s) - Courtesy Mariano Rocchi

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HMGA2 has long UTR (about 3,000 nt). HMGA2 can be potentially regulated by multiple miRNAs and one of well characterized miRNAs is let-7 family which contains at least five predicted bindings sites. MIRLET7E (Let-7) repression of HMGA2 expression at transcription and translation has been demonstrated in several different studies (Lee and Dutta 2007, Wang et al. 2007, Peng et al. 2008). Inverse association of Let-7 and HMGA2 is an important regulation mechanism in normal development and abnormal tumorigensis (Park et al. 2007, Shell et al. 2007).

DNA/RNA Description hooks) linked to the carboxy-terminal acidic domain that does not activate transcription. 5 exons, spans approximately 160 kb; a sixth alternative terminal exon within intron 3 has been described Transcription RNA: 4.1 kb. Transcription initiated from two different promoter regions. A polymorphic dinucleotide repeat HMGA2 can directly regulate expression of many genes. upstream of the ATG start codon strongly regulates Specific recognition of AT-rich DNA sequences by HMGA2 HMGA2 expression. Moreover, HMGA2 is was reporte by a SELEX study. The relative heights are proportional to their frequencies shown in the 71 SELEX controlled by negatively acting regulatory elements sequences (Cui and Leng 2007). within the 3'UTR Expression Protein Fetal tissues: expression in various tissues, prominent in kidney, liver and uterus; adult tissues: no expression except in lung and kidney; tumors: expression in benign mesenchymal tumor tissues correlated to 12q15 rearrangements; expressed in malignant tumours (e.g., in breast tumours, pancreas tumours, ovarian cancer, lung tumours, colorectal cancer, nerve system tumours, oral cavity squamous

cell cancer). Description Localisation 109 amino acids; three DNA binding domains (AT Nuclear

Inverse expression pattern of HMGA2 and let-7 family in developmental and adulthood stages as well as neoplastic change (Park, Shell et al. 2007).

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Immunohistochemistry shows that HMGA2 is specifically expressed and located in nucleus. Photomicrographs illustrate strong immunoreactivity for HMGA2 in leiomyoma with t(12;14) translocation and high grade serous ovarian carcinoma (Wu and Wei 2013, Bertsch et al. 2014).

It is widely accepted that functional CDKN2A (p16INK4a) and RB1 (pRb) as well as the HMGA2, which accumulate at E2F target promoters during senescence, are critically required for SAHF arrangement (Narita et al. 2006).

HMGA2 is regulated by non-coding miRNAs and coding genes. As a non-histone nuclear transcription regulator, HMGA2 has a broad influence in many gene expression, mainly target at epithelial-to-mesenchymal transition (EMT), cell proliferation, DNA damage repair, stem cell self-renewal and differentiation, as well as tumorigenesis of many benign and malignant mesenchymal and epithelial tumors (Wu and Wei 2013).

HMGA2 regulates stem cell potential for self-renewal. HMGA2 seems to be a major regulator of INK4a/ARF expression. HMGA2 reduces INK4A and ARF expression. HMGA2 binds to the Junb locus. As JUNB promotes INK4A/ARF expression in stem cells, thus promoting stem cell self-renewal. Increase in let-7 expression results in the downregulation of HMGA2 and the derepression of the INK4a/ARF and activation of p16INK4a expression in self-renewing cells. In Hmga2-deficient mice, it shows reduced stem cell numbers and self-renewal. Furthermore, p16(Ink4a) and p19(Arf) expression were increased in Hmga2-deficient fetal and young-adult stem cells, and deletion of p16(Ink4a) and/or p19(Arf) partially restored self-renewal capacity. (Yu et al. 2007, Nishino et al. 2008).

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Function for t(3;12): HMGIC-LPP (LPP: lipoma preferred partner; 3q27-28); a gene located in 13q, LHFP Architectural factor, non histone, preferential (lipoma HMGIC fusion partner) was found to be binding to AT rich sequences in the minor groove of fused with HMGIC in one case of lipoma; one DNA helix; the precise function remains to be lipoma displayed fusion of HMGA2 exon 4 with a elucidated; probable role in regulation of cell sequence from intron 4, indicating abnormal proliferation. splicing; HMGA2-CMKOR1 in three cases with Homology aberrations involving 2q35-37 and 12q13-15; Member of the HMGI protein family. HMGA2-NFIB in one lipoma; Abnormal protein Mutations HMGIC-LPP; the three AT hook domains at the aminoterminal of HMGIC are fused to the LIM Germinal domain of LPP; another fusion protein due to the Deletion of HMGIC in mutant mice or transgenic fusion of HMGIC with a putative gene located at 'knock out' mice for the first two exons of HMGIC 15q24 predicted to encode a protein with a have the "pigmy" phenotype: low birth weight, serine/threonine-rich domain has also been craniofacial defects, adipocyte hypoplasia adult described body weight about 40% of normal; mice with a Oncogenesis partial or complete deficiency of HMGA2 resisted the relevance of the exact role LPP in the HMGA2- diet-induced obesity implicating a role of the gene in LPP fusion is not established yet, but the fat cell proliferation; truncations of mouse Hmga2 in transactivation functions of the LPP LIM domains is transgenic mice result in somatic overgrowth and, in retained in the fusion protein and the fusion protein particular, increased abundance of fat and lipomas; can function as a transcription factor; the truncation overexpression of the HMGA2 gene in transgenic of HMGA2 by itself may have a role in the mice leads to the onset of pituary adenomas secreting tumorigenesis prolactic and growth hormone; HMGA2-null mice had very few spermatids and complete absence of Uterine leiomyoma (uterine fibroids) spermatozoa. Disease 8-year-old boy had a de novo pericentric inversion benign mesenchymal tumors of chromosome 12, with breakpoints at p11.22 and Prognosis q14.3. good The phenotype included extreme somatic overgrowth, advanced endochondral bone and dental Cytogenetics ages, a cerebellar tumour, and multiple lipomas. His approximately 40% of uterine leiomyomas have chromosomal inversion was found to truncate structural chromosomal rearrangements, about 10% HMGA2, which maps to the 12q14.3 breakpoint. of which involve 12q15 (translocations, inversions, deletions...); the most frequent anomaly is Implicated in t(12;14)(q15;q23-24) Hybrid/Mutated gene MESENCHYMAL BENIGN TUMORS in a majority of cases, there is no fusion gene: the as follows: breakpoint is located 10 kb up to 100 kb 5' to Lipoma HMGIC; the recombinational repair gene RAD51B is a candidate to be the partner gene of HMGIC in Disease t(12;14). In two cases (out of 81 primary tumors) benign adipocyte tumor exon 7 of RAD51B was fused in frame to either exon Prognosis 2 or 3 of the HMGA2 gene; in one case with good paracentric inversion, HMGIC exon 3 was fused to Cytogenetics ALDH2 exon 13 (12q24.1); in one case (no various rearrangements involving 12q15 cytogenetic analysis) HMGIC exon 3 was fused to (translocations, inversions, deletions...); reciprocal COX6C 3' UTR (8q22-23); in one case, with translocations involve 12q15 with different partners apparently normal karyotype, exon 3 of HMGIC was such as chromosomes 1, 2, 3, 7, 10, 11, 13, 15, 17, fused to retrotransposon-like sequences RTVLH 3' 21, X; the most frequent anomaly is t(3;12)(q27- LTRs; three fusion transcripts contained 3' cryptic 28;q15); cryptic rearrangements, such as paracentric exonic sequences present in intron 3 of the HMGA2 inversions not detectable by conventional gene (breakpoints downstream of exons 3 or 4), cytogenetics but detectable by FISH, have been suggesting that they are due to alternative splicing; described. one case displayed fusion of the first two exons of Hybrid/Mutated gene

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HMGA2 to the 3' portion of the CCNB1IP1/C14orf18/HEI10 gene conventional cytogenetics but detectable by FISH have been described. Hybrid/Mutated gene in two cases with apparently normal karyotypes, exon 3 of HMGIC was fused to retrotransposon- like sequences RTVLH 3' LTRs; in cases with t(3;12)(q27-28;q14-15) (see lipomas), a fusion of Abnormal protein HMGA2-LPP was described; only 1/61 cases with HMGIC-ALDH2: ALDH2 contribution was only 10 normal karyotype displayed HMGA2-LPP fusion; amino acids; three cases with rearrangements involving 12q14- Oncogenesis 15 and 13q12-14 lacked rearrangements of HMGIC-ALDH2: it is suggested that the truncation HMGA2-LHFP of HMGIC, rather than fusion may be responsible for Endometrial polyps tumorigenesis; the 3' untranslated region may stabilize the HMGIC messenger RNA Disease uterine benign tumors Pleomorphic adenoma of the salivary Prognosis gland (or mixed salivary gland tumor) good Disease Cytogenetics benign tumors from the major or minor salivary various rearrangements involving 12q15 leading to glands HMGIC dysregulation; cryptic rearrangements such Prognosis as paracentric inversions not detectable by good conventional cytogenetics but detectable by FISH Cytogenetics have been described; in one case, HMGIC was approximately 12% of pleomorphic adenomas of amplified and overexpressed salivary glands show abnormalities involving Myofibroblastic inflammatory tumor HMGIC in 12q15; the most frequent aberration is Disease t(9;12)(p24.1;q15) benign mesenchymal tumors Hybrid/Mutated gene Prognosis in t(9;12): HMGIC-NFIB fusion; another type of good fusion HMGIC-FHIT (3p14.2) has also been described Cytogenetics in one case, a complex rearrangement involving Pulmonary chondroid hamartoma of chromosomes 12 (in 12q15), 4 and 21 was described the lung Hybrid/Mutated gene Disease an aberrant transcript was produced by the fusion of benign mesenchymal tumors of the lung HMGIC exon 3 to an ectopic sequence originating Prognosis from the third intron of HMGIC good Chondrolipoangioma Cytogenetics Disease various rearrangements involving 12q15 leading to a rare benign type of mesenchyomas composed HMGIC dysregulation; cryptic rearrangements such predominantly of cartilage and adipose tissue with as paracentric inversions not detectable by vascular elements and myxoid elements

HMGA2 and MED12 mutations are mutually exclusive and are the two independent factors for tumorigenesis of leiomyoma (Bertsch et al. 2014). Cytogenetics

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One case demonstrated t(12;15)(q13;q26). FISH rather good; borderline malignancy; locally analysis revealed rearrangement of chromosomes 2, aggressive, rarely metastasizes 12 and 15 and HMGA2. Cytogenetics Chondromas supernumerary ring or giant marker chromosomes Disease containing 12q14-15 amplification (surrounding MDM2); HMGIC is frequently amplified together benign cartilage tumours with MDM2; rearrangement of HMGA2, in addition Cytogenetics to amplification has been described HMGA2 was expressed in 4/6 soft tissue Hybrid/Mutated gene chondromas (all with 12q-rearrangements ectopic sequences from 12q14-15, 1q24, 11q14, and cytogenetically), three cases showed truncated chromosome 2 was shown to be fused to HMGA2 (exons 1-3) transcripts, one case displayed a exon 2 or 3 t(3;12)(q27;q15) and RT-PCR demonstrated a HMGA2-LPP fusion transcript composed of Uterine leiomyosarcoma HMGA2 exons 1-3 and LPP exons 9-11. Disease Hyaline vascular Castleman's malignant counterpart of uterine leiomyoma disease Prognosis Cytogenetics poor one case with der(6)t(6;12)(q23;q15)del(12)(q15) is Cytogenetics described. 12q13-15 region is recurrently amplified Hybrid/Mutated gene Hybrid/Mutated gene a combined immunologic-cytogenetic approach HMGA2 amplified within this region demonstrated HMGA2 rearrangement in follicular Osteosarcoma dendritic cells Disease Prolactinoma malignant tumor Disease Hybrid/Mutated gene prolactin-secreting pituary adenoma, non- in one osteosarcoma cell line (OsA-Cl) the three metastasizing DNA binding domains of HMGIC fused to the Cytogenetics keratan sulfate protein glycan gene LUM (12q22- trisomy 12 nonrandom finding in pituary adenomas 23); LUM was fused out of frame, and only 3 amino Hybrid/Mutated gene acids were fused to HMGIC; in addition, the HMGA2 locus amplified in 7/8 prolactinomas rearranged gene was amplified Aggressive angiomyxoma of the Myelofibrosis with myeloid vulva metaplasia Disease Disease myxoid mesenchymal neoplasm rare chronic myeloproliferative disorder Prognosis Prognosis infiltrative neoplasm, locally destructive variable recurrences, no metastatic potential Cytogenetics Cytogenetics one case with t(4;12)(q32;q15) and one case with one case displayed t(8;12)(p12;q15) t(5;12)(p14;q15) Hybrid/Mutated gene Hybrid/Mutated gene FISH demonstrated a breakpoint 3' of the gene, the FISH analysis suggested breakpoint in HMGA2, tumour expressed HMGA2 RT-PCR revealed that HMGA2 is expressed in blood mononuclear cells from patients with this MALIGNANT TUMORS as follows: disease Well-differentiated liposarcoma Acute lymphoblastic leukaemia Disease Disease malignant adipocyte tumor; peripheral or Heterogenous disease that arises in precursor B or T retroperitoneal location cells

Prognosis Cytogenetics

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One case with a t(9;12)(p22;q14), frequent deletions Breast Cancer at 12q14.3 Disease Hybrid/Mutated gene Serous carcinoma arising from fallopian tube t(9;12): FISH analysis indicated a breakpoint in the secretory epithelia. 5' region of the gene, RT-PCR showed Oncogenesis overexpression of HMGA2 lacking the HMGA2 gene and protein are highly expressed in carboxyterminal tail; deletions covering the 5' end of metastatic breast cancer cells. HMGA2 as an HMGA2 important regulator of PAR1-mediated invasion. High-grade serous carcinoma of the Inhibition of PAR1 signaling suppresses HMGA2- fallopian tubes driven invasion in breast cancer cells (Yang et al. 2015). Disease Colon Cancer Serous carcinoma arising from fallopian tube secretory epithelia. Disease Colonic adenocarcinoma. Oncogenesis Overexpression of HMGA2 regulated by several Oncogenesis genetic mechanism, including CTNNB1 (β - HMGA2 delays the clearance of H2AFX(γ-H2AX) Catenin), TGF- β, miRNAs. Currently well definied in colon cancer. miRNAs including let-7 and MIR-182. Overexpression of HMGA2 is associated with MiR-182 promotes HMGA2 expression through metastasis and unequivocally occurred in parallel negative regulation of BRCA1 (Moskwa et al. 2011, with reduced survival rates of patients with Liu et al. 2012). colorectal carcinoma (Wang et al. 2011). HMGA2 regulates several EMT genes including Lung Cancer STC2 and LUM (Wu et al. 2011). Overexpression of HMGA2 is associated with early Disease tumorigenesis, tumor cell proliferation, invasion and Non-small-cell lung cancer (NSCLC) worse outcome through regulation of cell cycle, Oncogenesis epithelial to mesenchymal transition (Wu et al. HMGA2 can operate as competing endogenous 2011). RNA (ceRNA) for the let-7 microRNA (miRNA) family, suggesting that Hmga2 affects let-7 activity Pancreatic carcinoma by altering miRNA targeting. Disease HMGA2 promotes the transformation of lung cancer Pancreatic ductal carcinoma. cells independent of protein-coding function. Tgfbr3 Oncogenesis expression is regulated by the Hmga2 ceRNA through differential recruitment to Argonaute 2 Overexpression of HMGA2 promote EMT by regulation of SNAIL, SLUG, SIP1, TCF3 (AGO2), and TGF-β signalling driven by Tgfbr3 is (E12/E47), and ZEB1 (Watanabe et al. 2009). important for Hmga2 to promote lung cancer progression (Kumar et al. 2014). HMGA2 nuclear immunoreactivity correlates positively with lymph node metastases and high tumor grade (Hristov et al. 2009). Breakpoints See below.

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Up to 21 partners have a breakpoint with HMGA2 are summarized. The majority of this non-random translocations were found to be in mesenchymal neoplasia (Wu and Wei 2013). Mertens F, Mandahl N, Panagopoulos I. Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome References aberrations involving 2q35-37 and 12q13-15. Int J Oncol. Abe N, Watanabe T, Suzuki Y, Matsumoto N, Masaki T, 2002 Aug;21(2):321-6 Mori T, Sugiyama M, Chiappetta G, Fusco A, Atomi Y. An Cerignoli F, Ambrosi C, Mellone M, Assimi I, di Marcotullio increased high-mobility group A2 expression level is L, Gulino A, Giannini G. HMGA molecules in neuroblastic associated with malignant phenotype in pancreatic exocrine tumors. Ann N Y Acad Sci. 2004 Dec;1028:122-32 tissue. Br J Cancer. 2003 Dec 1;89(11):2104-9 Chieffi P, Battista S, Barchi M, Di Agostino S, Pierantoni Akai T, Ueda Y, Sasagawa Y, Hamada T, Date T, Katsuda GM, Fedele M, Chiariotti L, Tramontano D, Fusco A. S, Iizuka H, Okada Y, Chada K. High mobility group I-C HMGA1 and HMGA2 protein expression in mouse protein in astrocytoma and glioblastoma. Pathol Res Pract. spermatogenesis. Oncogene. 2002 May 16;21(22):3644-50 2004;200(9):619-24 Cho YL, Bae S, Koo MS, Kim KM, Chun HJ, Kim CK, Ro Anand A, Chada K. In vivo modulation of Hmgic reduces DY, Kim JH, Lee CH, Kim YW, Ahn WS. Array comparative obesity. Nat Genet. 2000 Apr;24(4):377-80 genomic hybridization analysis of uterine leiomyosarcoma. Andrieux J, Demory JL, Dupriez B, Quief S, Plantier I, Gynecol Oncol. 2005 Dec;99(3):545-51 Roumier C, Bauters F, Laï JL, Kerckaert JP. Dysregulation Cokelaere K, Debiec-Rychter M, De Wolf-Peeters C, and overexpression of HMGA2 in myelofibrosis with myeloid Hagemeijer A, Sciot R. Hyaline vascular Castleman's metaplasia. Genes Chromosomes Cancer. 2004 disease with HMGIC rearrangement in follicular dendritic Jan;39(1):82-7 cells: molecular evidence of mesenchymal tumorigenesis. Arlotta P, Tai AK, Manfioletti G, Clifford C, Jay G, Ono SJ. Am J Surg Pathol. 2002 May;26(5):662-9 Transgenic mice expressing a truncated form of the high Crombez KR, Vanoirbeek EM, Van de Ven WJ, Petit MM. mobility group I-C protein develop adiposity and an Transactivation functions of the tumor-specific HMGA2/LPP abnormally high prevalence of lipomas. J Biol Chem. 2000 fusion protein are augmented by wild-type HMGA2. Mol May 12;275(19):14394-400 Cancer Res. 2005 Feb;3(2):63-70 Ashar HR, Fejzo MS, Tkachenko A, Zhou X, Fletcher JA, Cui T, Leng F. Specific recognition of AT-rich DNA Weremowicz S, Morton CC, Chada K. Disruption of the sequences by the mammalian high mobility group protein architectural factor HMGI-C: DNA-binding AT hook motifs AT-hook 2: a SELEX study. Biochemistry. 2007 Nov fused in lipomas to distinct transcriptional regulatory 13;46(45):13059-66 domains. Cell. 1995 Jul 14;82(1):57-65 Park SM, Shell S, Radjabi AR, Schickel R, Feig C, Saito H, Takenaka H, Yoshida S, Tsubokawa T, Ogata A, Boyerinas B, Dinulescu DM, Lengyel E, Peter ME. Let-7 Imanishi F, Imanishi J. Prevention from naturally acquired prevents early cancer progression by suppressing viral respiratory infection by interferon nasal spray. expression of the embryonic gene HMGA2. Cell Cycle. 2007 Rhinology. 1985 Dec;23(4):291-5 Nov 1;6(21):2585-90 Borrmann L, Seebeck B, Rogalla P, Bullerdiek J. Human Dahlén A, Mertens F, Rydholm A, Brosjö O, Wejde J, HMGA2 promoter is coregulated by a polymorphic Mandahl N, Panagopoulos I. Fusion, disruption, and dinucleotide (TC)-repeat. Oncogene. 2003 Feb 6;22(5):756- expression of HMGA2 in bone and soft tissue chondromas. 60 Mod Pathol. 2003 Nov;16(11):1132-40 Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M,

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Mueller GC, Gusberg SB, Stone A. The Mary Lasker Hernando E, Wei JJ. MiR-182 overexpression in Conference, on growth factors in hormone-related tumors. tumourigenesis of high-grade serous ovarian carcinoma. J Cancer Res. 1991 Aug 1;51(15):4114-20 Pathol. 2012 Oct;228(2):204-15 Fedele M, Battista S, Kenyon L, Baldassarre G, Fidanza V, Meza-Zepeda LA, Berner JM, Henriksen J, South AP, Klein-Szanto AJ, Parlow AF, Visone R, Pierantoni GM, Pedeutour F, Dahlberg AB, Godager LH, Nizetic D, Forus Outwater E, Santoro M, Croce CM, Fusco A. A, Myklebost O. Ectopic sequences from truncated HMGIC Overexpression of the HMGA2 gene in transgenic mice in liposarcomas are derived from various amplified leads to the onset of pituitary adenomas. Oncogene. 2002 chromosomal regions. Genes Chromosomes Cancer. 2001 May 9;21(20):3190-8 Jul;31(3):264-73 Finelli P, Pierantoni GM, Giardino D, Losa M, Rodeschini O, Mine N, Kurose K, Konishi H, Araki T, Nagai H, Emi M. Fedele M, Valtorta E, Mortini P, Croce CM, Larizza L, Fusco Fusion of a sequence from HEI10 (14q11) to the HMGIC A. The High Mobility Group A2 gene is amplified and gene at 12q15 in a uterine leiomyoma. Jpn J Cancer Res. overexpressed in human prolactinomas. Cancer Res. 2002 2001 Feb;92(2):135-9 Apr 15;62(8):2398-405 Miyazawa J, Mitoro A, Kawashiri S, Chada KK, Imai K. Gattas GJ, Quade BJ, Nowak RA, Morton CC. HMGIC Expression of mesenchyme-specific gene HMGA2 in expression in human adult and fetal tissues and in uterine squamous cell carcinomas of the oral cavity. Cancer Res. leiomyomata. Genes Chromosomes Cancer. 1999 2004 Mar 15;64(6):2024-9 Aug;25(4):316-22 Kolárová J, Hroch M. [The effect of atropine, quinuclidinyl Hauke S, Flohr AM, Rogalla P, Bullerdiek J. Sequencing of benzilate and their antidote tetrahydroaminoacridine on intron 3 of HMGA2 uncovers the existence of a novel exon. adhesion and spreading in cells cultured in vitro]. Sb Ved Pr Genes Chromosomes Cancer. 2002 May;34(1):17-23 Lek Fak Karlovy Univerzity Hradci Kralove Suppl. 1988;31(4):459-65 Hauke S, Rippe V, Bullerdiek J. Chromosomal rearrangements leading to abnormal splicing within intron 4 Hideshima T, Okada N, Okada H. Expression of HRF20, a of HMGIC? Genes Chromosomes Cancer. 2001 regulatory molecule of complement activation, on peripheral Mar;30(3):302-4 blood mononuclear cells. Immunology. 1990 Mar;69(3):396- 401 Hess JL. Chromosomal translocations in benign tumors: the HMGI proteins. Am J Clin Pathol. 1998 Mar;109(3):251-61 Nilsson M, Panagopoulos I, Mertens F, Mandahl N. Fusion of the HMGA2 and NFIB genes in lipoma. Virchows Arch. Cotugna N. Predictors of nutrition supplement use in the 2005 Nov;447(5):855-8 elderly. Part I: A review of the literature. J Nutr Elder. 1989;8(3-4):3-13 Templeton JG, Cocker JE, Crawford RJ, Forwell MA, Sandilands GP. Fc gamma-receptor blocking antibodies in Hui P, Li N, Johnson C, De Wever I, Sciot R, Manfioletti G, hyperimmune and normal pooled gammaglobulin. Lancet. Tallini G. HMGA proteins in malignant peripheral nerve 1985 Jun 8;1(8441):1337 sheath tumor and synovial sarcoma: preferential expression of HMGA2 in malignant peripheral nerve sheath tumor. Mod Nucci MR, Weremowicz S, Neskey DM, Sornberger K, Pathol. 2005 Nov;18(11):1519-26 Tallini G, Morton CC, Quade BJ. Chromosomal translocation t(8;12) induces aberrant HMGIC expression in Kazmierczak B, Dal Cin P, Sciot R, Van den Berghe H, aggressive angiomyxoma of the vulva. Genes Bullerdiek J. Inflammatory myofibroblastic tumor with Chromosomes Cancer. 2001 Oct;32(2):172-6 HMGIC rearrangement. Cancer Genet Cytogenet. 1999 Jul 15;112(2):156-60 Patel HS, Kantarjian HM, Bueso-Ramos CE, Medeiros LJ, Haidar MA. Frequent deletions at 12q14.3 chromosomal Kools PF, Van de Ven WJ. Amplification of a rearranged locus in adult acute lymphoblastic leukemia. Genes form of the high-mobility group protein gene HMGIC in OsA- Chromosomes Cancer. 2005 Jan;42(1):87-94 CI osteosarcoma cells. Cancer Genet Cytogenet. 1996 Oct 1;91(1):1-7 Peng Y, Laser J, Shi G, Mittal K, Melamed J, Lee P, Wei JJ. Antiproliferative effects by Let-7 repression of high-mobility Divo AA, Geary TG, Davis NL, Jensen JB. Nutritional group A2 in uterine leiomyoma. Mol Cancer Res. 2008 requirements of Plasmodium falciparum in culture. I. Apr;6(4):663-73 Exogenously supplied dialyzable components necessary for continuous growth. J Protozool. 1985 Feb;32(1):59-64 Petit MM, Mols R, Schoenmakers EF, Mandahl N, Van de Ven WJ. LPP, the preferred fusion partner gene of HMGIC Kurose K, Mine N, Iida A, Nagai H, Harada H, Araki T, Emi in lipomas, is a novel member of the LIM protein gene M. Three aberrant splicing variants of the HMGIC gene family. Genomics. 1996 Aug 15;36(1):118-29 transcribed in uterine leiomyomas. Genes Chromosomes Cancer. 2001 Feb;30(2):212-7 Pierantoni GM, Santulli B, Caliendo I, Pentimalli F, Chiappetta G, Zanesi N, Santoro M, Bulrich F, Fusco A. Lemke I, Rogalla P, Grundmann F, Kunze WP, Haupt R, HMGA2 locus rearrangement in a case of acute Bullerdiek J. Expression of the HMGA2-LPP fusion lymphoblastic leukemia. Int J Oncol. 2003 Aug;23(2):363-7 transcript in only 1 of 61 karyotypically normal pulmonary chondroid hamartomas. Cancer Genet Cytogenet. 2002 Oct Quade BJ, Weremowicz S, Neskey DM, Vanni R, Ladd C, 15;138(2):160-4 Dal Cin P, Morton CC. Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine Ligon AH, Moore SD, Parisi MA, Mealiffe ME, Harris DJ, leiomyomata with rearrangements in 12q15. Cancer Res. Ferguson HL, Quade BJ, Morton CC. Constitutional 2003 Mar 15;63(6):1351-8 rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. Am J Rogalla P, Kazmierczak B, Meyer-Bolte K, Tran KH, Hum Genet. 2005 Feb;76(2):340-8 Bullerdiek J. The t(3;12)(q27;q14-q15) with underlying HMGIC-LPP fusion is not determining an adipocytic Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, phenotype. Genes Chromosomes Cancer. 1998 Jun;22(2):100-4

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 411

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Rogalla P, Lemke I, Bullerdiek J. Absence of HMGIC-LHFP and methylprednisolone in renal transplantation. Transplant fusion in pulmonary chondroid hamartomas with aberrations Proc. 1987 Feb;19(1 Pt 3):1933-4 involving chromosomal regions 12q13 through 15 and 13q12 through q14. Cancer Genet Cytogenet. 2002 Wanschura S, Dal Cin P, Kazmierczak B, Bartnitzke S, Van Feb;133(1):90-3 den Berghe H, Bullerdiek J. Hidden paracentric inversions of chromosome arm 12q affecting the HMGIC gene. Genes Schoenberg Fejzo M, Ashar HR, Krauter KS, Powell WL, Chromosomes Cancer. 1997 Apr;18(4):322-3 Rein MS, Weremowicz S, Yoon SJ, Kucherlapati RS, Chada K, Morton CC. Translocation breakpoints upstream of the Babu GR, Reddy GR, Chetty CS. Perturbations in nitrogen HMGIC gene in uterine leiomyomata suggest dysregulation metabolism of brain and liver of rat following repeated of this gene by a mechanism different from that in lipomas. benthiocarb administration. Biochem Int. 1989 Genes Chromosomes Cancer. 1996 Sep;17(1):1-6 Jun;18(6):1253-68 Schoenmakers EF, Huysmans C, Van de Ven WJ. Allelic Wu J, Wei JJ. HMGA2 and high-grade serous ovarian knockout of novel splice variants of human recombination carcinoma. J Mol Med (Berl). 2013 Oct;91(10):1155-65 repair gene RAD51B in t(12;14) uterine leiomyomas. Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Cancer Res. 1999 Jan 1;59(1):19-23 Muller W, Liu J, Wei JJ. HMGA2 overexpression-induced Tomiyama S, Nonaka M, Yagi T, Goto Y, Ikezono T. ovarian surface epithelial transformation is mediated [Development of acute endolymphatic hydrops following through regulation of EMT genes. Cancer Res. 2011 Jan secondary endolymphatic sac immune response. I: Short- 15;71(2):349-59 term observation]. Nihon Jibiinkoka Gakkai Kaiho. 1991 Yang E, Cisowski J, Nguyen N, O'Callaghan K, Xu J, Mar;94(3):333-42 Agarwal A, Kuliopulos A, Covic L. Dysregulated protease Takahashi T, Nagai N, Oda H, Ohama K, Kamada N, activated receptor 1 (PAR1) promotes metastatic Miyagawa K. Evidence for RAD51L1/HMGIC fusion in the phenotype in breast cancer through HMGA2. Oncogene. pathogenesis of uterine leiomyoma. Genes Chromosomes 2016 Mar 24;35(12):1529-40 Cancer. 2001 Feb;30(2):196-201 Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu Van Dorpe J, Dal Cin P, Weremowicz S, Van Leuven F, de X, Su F, Lieberman J, Song E. let-7 regulates self renewal Wever I, Van den Berghe H, Fletcher CD, Sciot R. and tumorigenicity of breast cancer cells. Cell. 2007 Dec Translocation of the HMGI-C ( HMGA2) gene in a benign 14;131(6):1109-23 mesenchymoma (chondrolipoangioma). Virchows Arch. Zhou X, Benson KF, Ashar HR, Chada K. Mutation 2002 May;440(5):485-90 responsible for the mouse pygmy phenotype in the Wang T, Zhang X, Obijuru L, Laser J, Aris V, Lee P, Mittal developmentally regulated factor HMGI-C. Nature. 1995 K, Soteropoulos P, Wei JJ. A micro-RNA signature Aug 31;376(6543):771-4 associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chromosomes Cancer. This article should be referenced as such: 2007 Apr;46(4):336-47 Wei JJ. HMGA2 (high mobility group AT-hook 2). Atlas De Vecchi A, Tarantino A, Montagnino G, Egidi F, Vegeto Genet Cytogenet Oncol Haematol. 2016; 20(7):403-412. A, Berardinelli L, Ponticelli C. A controlled prospective trial of triple therapy with low-dose azathioprine, cyclosporine,

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Gene Section Review

NDRG1 (N-myc downstream regulated 1) Maria A Nagai, Flavia R Mangone Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo; Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of São Paulo, Av. Dr. Arnaldo, 251, CEP 01296-000, São Paulo, Brazil.

Published in Atlas Database: October 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/NDRG1ID41512ch8q24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66057/10-2015-NDRG1ID41512ch8q24.pdf DOI: 10.4267/2042/66057 This article is an update of : Wissing M, Rosmus N, Carducci M, Kachhap S. NDRG1 (N-myc downstream regulated 1). Atlas Genet Cytogenet Oncol Haematol 2010;14(8)

It is a member of the NDRG family, consisting of Abstract NDRG1, NDRG2, NDRG3 and NDRG4 (of which Review on NDRG1, with data on DNA, on the three isoforms exist: NDRG-4B, NDRG-4Bvar and protein encoded, and where the gene is implicated. NDRG-4H), which are part of the alpha/beta hydrolase superfamily. Identity The members of the NDRG family share 52-65% amino acid identity. Other names: CAP43, CMT4D, DRG-1, DRG1, The promoter region of all NDRG family members GC4, HMSNL, NDR1, NMSL, PROXY1, RIT42, contain CpG islands (Bandyopadhyay et al., 2004). RTP, Rit42, TARG1, TDD5 NDRG1 downregulation has been correlated with HGNC (Hugo) : NDRG1 DNA hypermethylation in some types of human Location : 8q24.22 cancer and cell lineages such as prostate, breast and gastric and also in sclerosis-affected brains (Li et al Location (base pair) , 2015; Huynh et al , 2014; Han et al , 2013; Chang Start: 133,237,171 bp from pter End: 133,302,022 bp et al , 2013). from pter (according to GRCh38/hg38 Dec_2013) Transcription DNA/RNA The DNA of NDRG1 contains 16 exons, see diagram for details about their location. Description The DNA encodes a 3.0 kb mRNA with a coding NDRG1 was mapped to human chromosome 8q24 region of 1.185 kb. and consists of 64,851 basepairs, starting at basepair 133,237,171 and ending at basepair 133,302,022 from the p-terminus.

DNA size: 64.85Kb; mRNA size: 3123 bp (NM_006096.3); 16 exons.

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testicular and intestinal cells. NDRG1 is mostly Protein found in epithelial cells. NDRG1 expression has Note been shown to be controlled by promoter CpG island Molecular weight: 42,835 KDa, 394aa methylation and histone acetylation. In addition, (NP_001128714.1) several transcription factors have been implicated in the NDRG1 transcriptional regulation, including Description homo- and heterodimers of MYC, MYCN and NDRG1 is a ~ 43 kD protein, composed of 394 MAX, androgen receptor (AR), TP53, and HIF1A. amino acids, with an iso-electric point of 5.7. Localisation NDRG1 has an alpha/beta hydrolase-fold motif, however, without a hydrolytic catalytic activity NDRG1 is primarily a cytoplasmic protein. 47.8% of required to function as hydrolases. The protein has the NDRG1 is expressed in the cytosol, 26.1% in the no apparent transmembrane domain (Kokame et al, nucleus (such as in prostate epithelial cells), and 1996). NDRG1 has several phosphorylation sites, 8.7% in the mitochondria (such as in proximal tubule among others a phosphopantetheine attachment site, cells in the kidney). protein kinase C, casein kinase II, tyrosine kinase, NDRG1 is also found in the adherens junctions. protein kinase A and calmodulin kinase II. Additionally, in intestinal and lactating breast Experimental studies have demonstrated that epithelia NDRG1 is located in the plasma NRDG1 is phosphorylated by Protein Kinase A and membrane. NDRG1 can also be found in vacuoles, Calmodulin kinase II, and is also a physiological the peroxisome, early and recycling endosomes, and substrate of SGK1 and GSK-3-beta kinase (Figure the cytoskeleton. 1), a kinase involved in cancer growth and Function progression. he C-terminal region of NDRG1 (residues 339-369) possess three tandem repeats of The exact function of NDRG1 is still unclear. The 10 amino acids, GTRSRSHTSE, (Zhou et al, 2001) expression of all members of the NDRG1 family has not present in the other members of the NDRG been correlated with different stages of family. These repeats with a histidine located differentiation from birth to adulthood. NDRG1 has between serine and threonine residues act as a been reported to be involved in different biological binding site for metal ions such as nickel and copper processes as cell proliferation, differentiation, (Zoroddu et al, 2001) (Figure 1). NDRG1 is also development, and stress response (Ellen et al., 2008). target for SOMOylation, preferentially by SUMO-2 There is evidence that NDRG1 expression peaks in isoform, in an acceptor site in residue Lys14. This the G1 and G2/M phases, and is lowest in the S modification does not affect the subcellular phase, and that this regulation might be associated to localization of NDRG1 but the protein stability by cell growth and differentiation. In fact, NDRG1 has increasing protein ubiquitination and degradation been shown to up regulates p21/WAF1 (Kovacevic (Lee and Kim, 2015) (Figure 1). et al, 2013) and NDRG1 expression is downregulated under conditions of increased cell Expression proliferation. NDRG1 is also described as a NDRG1 is relatively ubiquitously expressed in microtubule-associated protein, which may play an normal human cells, and especially highly expressed important role in maintaining spindle structure in prostate, brain, kidney, placenta, ovarian, thyroid, during cell division.

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Figure 1 - Schematic representation of the modular structure of NDRG1 - NDRG1 is target of phosphorylation by PKA, PKC, CaMKII. Residues that are phosphorylated by SGK1 and GSK3 and target of SUMOylation by SUMO-2 are indicated. PKA: Protein Kinase A; PKC: Protein Kinase C; CaMKII: Calmodulin Kinase II; SGK1: serum and glucocorticoid-regulated kinase 1; GSK3- Glycogen synthase kinase 3; SUMO-2: Small Ubiquitin-Like Modifier 2 .

The function of NDRG1 may be controlled at least APO A-I and A-II, and may be involved in lipid in part by phosphorylation. Phosphorylation at transport. residues Ser330 and Thr346 by SGK-1 is involved in Evidences obtained from global gene expression NF-κB signaling pathway inhibition probably analysis of breast cell lines with high endogenous affecting cell survival (Murakami et al, 2010). NDRG1 expression transduced with shRNA against NDRG1 has also been identified as a stress response NDRG1 suggested an involvement of NDRG1 with gene, upregulated by homocysteine and hypoxia. vesicle transport (Askautrud et al, 2014). Hif-1-dependent and independent mechanisms have In cancer, NDRG1 is reported to be a metastasis been implicated in NDRG1 induction. It is also suppressor gene which is downregulated in prostate, controlled by AP-1 transcription factors. When colon and breast cancers. exposed to stress, for example hypoxia, NDRG1 However, up-regulation of NDRG1 has also been may play a cytoprotective role in normal healthy associated to poor prognosis in breast, renal, cells. hepatocellular, and colorectal cancer, suggesting that NDRG1 is upregulated during colon epithelial cell it may play different role depending on cellular type differentiation. It is positively or negatively and context (Nagai. et al, 2001; Nishie et al, 2001; regulated by hormones such as androgens and Chua et al, 2007; Strzelczyk et al, 2009). estradiol, respectively. Small molecules such as N- Signaling Pathways hydroxy-N'-phenol-octane-1,8-diotic acid diamide, The widespread localization of NDRG1 might calcium ionophores like BAPTA, metal ions such as impact its involvement with diverse signaling Nickel and Cobalt, iron chelators and differentiating pathways. It has been demonstrated that NDRG1 agents like retinoic acid induce NDRG1 expression. interacts directly with NF-κB, PI3K/AKT/ mTOR, Additionally, NDRG1 is induced during cellular Ras/Raf/MEK/ERK, TGF-β; and Wnt/β-catenin DNA damage and endoplasmic reticulum stress. pathways independently with each pathway or by In the Schwann cells, NDRG1 is essential for myelin promoting a crosstalk between them (Sun J et al, sheath maintenance. Hence, NDRG1 is a 2013). multifunctional protein with roles that may be tissue- The nuclear translocation of the DNA binding and/or cell-type specific. subunit of NFκB, NFKB1 (p50), complexed with It has been found to be a Rab4a effector protein that RelA is reduced by NDRG1 as a consequence of the recruits to the recycling endosomes in the Trans induced degradation of IKBKB (IKK&beta), subunit Golgi network by binding to the lipid of the IκB kinase complex (Hosoi et al, 2009). The phosphotidylinositol 4-phosphate (PI4P), where it effect of NDRG1 on NFκB signaling pathway seems plays a role in the recycling of E-cadherin. NDRG1 to be dependent of phosphorylation at residues also interacts with HSP70. NDRG1 co-localizes with Ser330 and Thr346 by SGK1 (Murakami et al, 2010).

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Figure 2 - Modulators and Biological functions of NDRG1 - NDRG1 is involved in a variety of signaling pathways been positively or negatively regulated. As a consequence, diverse biological processes are modulated. HIF1, hypoxia inducible factor 1; c-Myc, v-myc avian myelocytomatosis viral oncogene homolog; AR, Androgen receptor; E2, -17β-estradiol; AP1, activator protein-1, p53, tumor suppressor protein p53; PTEN, phosphatase and tensin homolog; VEGF, vascular endothelial growth factor; CXCL8 (IL-8), interleukin-8; p21, cyclin-dependent kinase inhibitor 1A; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; pERK, extracellular signal-regulated kinases; SMAD4, SMAD family member 4; PI3K, phosphatidylinositol 3-kinase; AKT, v-akt murine thymoma viral oncogene homolog.

The expression of PTEN, a tumor suppressor gene Prostatic adenocarcinoma, breast described as inactivated in diverse types of human cancer, colorectal cancer, renal cell cancers, is also involved in tumor metastasis suppression and it was demonstrated that PTEN carcinoma, bladder carcinoma, targets NDRG1 in a PI3K dependent manner. It was pancreatic cancer, hepatocellular demonstrated that up regulation of PTEN increase carcinoma, thyroid carcinoma, and the level of NDRG1 and the inhibition of PTEN by glioma. shRNA also inhibits NDRG1 expression. This Prognosis blockage is reverted when the cells are treated with The association of NDRG1 and prognosis of cancer phospho-Akt inhibitor, evidencing a dependency of patients is controversial. Some studies have found PI3K/AKT pathway (Bandyopadhyay, et al, 2004). that downregulation of NDRG1 in cancer worsens In prostate epithelial cells NDRG1 expression the prognosis of cancer. There is an inverse increased phosphorylation of tumorigenic AKT, relationship in the levels of NDRG1 expression and ERK1/2 and SMAD2L and decreased PTEN levels the Gleason grade of the tumor in prostate cancer. A (Dixon et al, 2013). NDRG1 also has been associated high PTEN (a tumor suppressor which positively to up-regulation of SMAD4 that is responsible for regulates NDRG1) and NDRG1 expression nuclear translocation of effector SMADs upon TGFβ improves survival rates in patients with breast and receptor activation. Up regulation of SMAD4 has a prostate cancer. In patients with colorectal cancer, dual role both in TGFβ signaling, intermediating the the 2 year survival rate for patients with high induction of p21, and also blocking Ras signaling NDRG1-expression was 82.4%, while for patients pathway by inhibiting ERK phosphorylation with a low NDRG1-expression it was only 69.6%. In (Kovacevic et al, 2013) (Figure 2). pancreatic cancer patients, the median survival time Homology for patients with high NDRG1-expression was 24.7 months, while the median survival time for patients NDRG1 amino acid sequence is 53% homologous to with low NDRG1-expression was only 10.9 months. NDRG2, 62% to NDRG3, 62% to NDRG4, and 94% High expression of NDRG1 in colon tumors was homologous to the mouse analog, Ndr-1 (also known found to correlate with increased resistance to as TDD5). NDRG1 homologs have been found in irinotecan. Helianthus, Caenorhabditis, Xenopus and On the other hand, the positivity for NDRG1 Drosophilia. expression was associated to poor disease free and overall survival of breast cancer patients. Also, the Implicated in positivity of NDRG1 protein observed in breast

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cancer patients is associated with important clinic- cycle, instead of the biphasic expression in normal pathological variables for disease outcome, such as cells. PTEN expression is positively related to large tumor size, advanced clinical stage, lymph NDRG1 expression. NDRG1 is induced in cancer node metastasis and high tumor grade (SBR) (Nagai. cells by histone deacetylase inhibitors and DNA et al, 2001). An inverse correlation of NDGR1 and methyl transferase inhibitors indicating that NDRG1 ER and/or PR status has also been described (Leth- is regulated by chromatin modulation and DNA Larsen et al, 2009; Fotovati et al, 2006). methylation. Increase in protein level has been observed in thyroid Although NDRG1 has been reported to be carcinomas. Thyroid lesions showed higher downregulated in a variety of cancers, it has been immunohistochemical staining of NDRG1 as shown to be upregulated in hepatic, pancreatic and compared to normal and benign thyroid lesions that kidney cancers. Induction of NDRG1 in these tumors was correlated with more advanced tumor stages. is speculated to be in response to tumor stress or This increase of NDRG1 expression was correlated hypoxia and NDRG1 is proposed as a marker of with more advanced TNM stage (stages III and IV) tumor hypoxia. However, in pancreatic cancer, and an AMES high-risk category in patients with cellular differentiation and not hypoxia was thyroid carcinoma (Gerhard et al, 2010). demonstrated to be the determining factor for In hepatocellular carcinoma upregulation of NDRG1 NDRG1 expression. In renal cancer, induction of has been correlated with tumour aggressiveness and NDRG1 in the tumor tissue was restricted to poor patients' survival (Chua et al., 2007). infiltrating macrophages and not cancer cells. NDRG1 has been associated to breast cancer cells NDRG1 is suggested to be an early target for p53. differentiation both in vitro and in vivo. Endogenous Loss of p53 expression in cancer is suggested to expression of NDRG1 was associated to reduce NDRG1 expression. However, p53 knockout differentiation status of breast cancer cell lines and mice show expression of NDRG1, suggesting that when these cells were treated with the cellular there are other mechanisms regulating NDRG1 differentiation inducer, sodium butyrate, a levels. concomitant increase of NDRG1 and β-casein, a NDRG1 expression plays a role in vitro in primary marker of breast cell differentiation, expression was tumor growth in prostate, breast, and bladder cancer: observed. Moreover, the blockage of NDRG1 a higher expression of NDRG1 lowers the expression was also followed by β-casein reduction. proliferation rates of these cancers. In pancreatic and Also in breast cancer samples a close relationship bladder cancer cells, this reduction was proven in between NDRG1 and β-casein was found (Fotovati vivo: in pancreatic cells it was suggested that the et al, 2011). reduced proliferation was caused by NDRG1 by NDRG1 has been considered as a possible biomarker modulating tumor stroma and angiogenesis. NDRG1 to guide the decision of treatment of WHO grade II can recruit onto the recycling endosome in the Trans- glioma patients. Time to reintervention, assessed for Golgi network by binding to phosphotidylinositol 4- patients without immediate postoperative genotoxic phosphate. There, NDRG1 may be involved in the treatment and known progression and survival transport of various cargo back to the cells' surface. status, was significantly longer in the high NDRG1 At the molecular level, NDRG1 may stabilize the E- group. This group of tumors presented growth delay cadherin molecule by recycling it back to the cells' improving progression free surviva (Blaes et al, surface, thereby preventing tumor invasion. 2014). Hereditary Motor and Sensory Oncogenesis Neuropathy-Lom (HMSNL) / Charcot- NDRG1 aberrant expression has been reported in Marie-Tooth Disease (CMT 4D) different types of cancer, indication that it plays an important role in the tumorigenic process. However, Note both tumor suppressive and oncogenic functions Autosomal recessive mutation in NDRG1 is have been demonstrated for NDRG1, suggesting an responsible for HMSNL/CMT 4D inheritance. The impact of its tissue specific function. Gypsy founder mutation, homozygote R148X, also An inverse relationship exists between NDRG1 and called homozygote C564t is a causative mutation. In the oncogenes N-myc and c-myc, suggesting that patients with CMT disease, apart from the R148X members of the MYC family suppress expression of mutation, another disease-causing mutation was NDRG1. Experimental evidence exist that both N- identified, namely IVS8-1G>A (g.2290787G>A), myc and c-myc downregulate NDRG1 gene which results in skipping of exon 9. The homozygote expression by directly binding to NDRG1 promoter. phenotype of this mutation was very closely related NDRG1 is downregulated in colon, breast, prostate to the phenotype of HMSNL patients. and pancreatic neoplasms, by c-myc and N-myc An increased copy number (chr8: 134265065- transcription factors. In cancer cells, NDRG1 134271319) covering NDRG's1 exons 6-8 was expression is consistent through all phases in the cell detected in CMT individual. Heterozygous

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individuals for the locus duplication are carriers for Cangul H. Hypoxia upregulates the expression of the the disease while the homozygous are affected. Also, NDRG1 gene leading to its overexpression in various human cancers. BMC Genet. 2004 Sep 2;5:27 the presence of this duplication leads to a nonsense mutation at codon 223 affecting gene function Chang X, Zhang S, Ma J, Li Z, Zhi Y, Chen J, Lu Y, Dai D. Association of NDRG1 gene promoter methylation with (Okamoto et al, 2014). reduced NDRG1 expression in gastric cancer cells and Disease tissue specimens. Cell Biochem Biophys. 2013 A hereditary autosomal recessive disease, caused by May;66(1):93-101 demyelination of peripheral nerves. It is the most Chen B, Nelson DM, Sadovsky Y. N-myc down-regulated common form of demyelinating Charcot-Marie- gene 1 modulates the response of term human trophoblasts Tooth disease in the Roma population. to hypoxic injury. J Biol Chem. 2006 Feb 3;281(5):2764-72 Chua MS, Sun H, Cheung ST, Mason V, Higgins J, Ross Prognosis DT, Fan ST, So S. Overexpression of NDRG1 is an indicator Severe disability in adulthood. It begins consistently of poor prognosis in hepatocellular carcinoma. Mod Pathol. in the first decade of life with a gait disorder, 2007 Jan;20(1):76-83 followed by upper limb weakness in the second Cui DX, Zhang L, Yan XJ, Zhang LX, Xu JR, Guo YH, Jin decade and, in most subjects, by deafness setting in GQ, Gomez G, Li D, Zhao JR, Han FC, Zhang J, Hu JL, Fan in the third decade of life. Sensory loss affecting all DM, Gao HJ. A microarray-based gastric carcinoma modalities is present; both this and the motor prewarning system. World J Gastroenterol. 2005 Mar 7;11(9):1273-82 involvement predominating distally in the limbs. Skeletal deformity, particularly foot deformities, are Dixon KM, Lui GY, Kovacevic Z, Zhang D, Yao M, Chen Z, Dong Q, Assinder SJ, Richardson DR. Dp44mT targets the frequent. AKT, TGF-β and ERK pathways via the metastasis Atherosclerosis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells. Br J Cancer. 2013 Feb 5;108(2):409- Note 19 Patients with HMSNL were found to have a high Ellen TP, Ke Q, Zhang P, Costa M. NDRG1, a growth and total cholesterol: HDL-C ratio. cancer related gene: regulation of gene expression and function in normal and disease states. Carcinogenesis. Disease 2008 Jan;29(1):2-8 Atherosclerosis is an important factor for the development of cardiovascular diseases, like Fotovati A, Fujii T, Yamaguchi M, Kage M, Shirouzu K, Oie S, Basaki Y, Ono M, Yamana H, Kuwano M. 17Beta- myocardial infarction and angina pectoris. NDRG1 estradiol induces down-regulation of Cap43/NDRG1/Drg-1, contributes to HDL-C (high-density lipoprotein- a putative differentiation-related and metastasis suppressor cholesterol) levels most likely by its gene, in human breast cancer cells. Clin Cancer Res. 2006 phosphopantetheine-binding domain interacting May 15;12(10):3010-8 with the high-density lipoproteins apolipoprotein A- Gerhard R, Nonogaki S, Fregnani JH, Soares FA, Nagai I and A-II MA. NDRG1 protein overexpression in malignant thyroid neoplasms. Clinics (Sao Paulo). 2010 Jun;65(8):757-62 References Gómez-Casero E, Navarro M, Rodríguez-Puebla ML, Larcher F, Paramio JM, Conti CJ, Jorcano JL. Regulation of Agarwala KL, Kokame K, Kato H, Miyata T. Phosphorylation the differentiation-related gene Drg-1 during mouse skin of RTP, an ER stress-responsive cytoplasmic protein. carcinogenesis. Mol Carcinog. 2001 Oct;32(2):100-9 Biochem Biophys Res Commun. 2000 Jun 16;272(3):641-7 Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 Askautrud HA, Gjernes E, Gunnes G, Sletten M, Ross DT, as a differentiation-related, putative metastatic suppressor Børresen-Dale AL, Iversen N, Tranulis MA, Frengen E. gene in human colon cancer. Cancer Res. 2000 Feb Global gene expression analysis reveals a link between 1;60(3):749-55 NDRG1 and vesicle transport. PLoS One. 2014;9(1):e87268 Han LL, Hou L, Zhou MJ, Ma ZL, Lin DL, Wu L, Ge YL. Aberrant NDRG1 methylation associated with its decreased Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, expression and clinicopathological significance in breast Miura K, Takano Y, Saito K, Commes T, Piquemal D, cancer. J Biomed Sci. 2013 Jul 30;20:52 Watabe M, Gross S, Wang Y, Huggenvik J, Watabe K. PTEN up-regulates the tumor metastasis suppressor gene Hosoi F, Izumi H, Kawahara A, Murakami Y, Kinoshita H, Drg-1 in prostate and breast cancer. Cancer Res. 2004 Nov Kage M, Nishio K, Kohno K, Kuwano M, Ono M. N-myc 1;64(21):7655-60 downstream regulated gene 1/Cap43 suppresses tumor Blaes J, Weiler M, Sahm F, Hentschel B, Osswald M, growth and angiogenesis of pancreatic cancer through Czabanka M, Thomé CM, Schliesser MG, Pusch S, Luger attenuation of inhibitor of kappaB kinase beta expression. S, Winkler F, Radbruch A, Jugold M, Simon M, Steinbach Cancer Res. 2009 Jun 15;69(12):4983-91 JP, Schackert G, Tatagiba M, Westphal M, Tonn JC, Hunter M, Angelicheva D, Tournev I, Ingley E, Chan DC, Gramatzki D, Pietsch T, Hartmann C, Glimm H, Vajkoczy P, Watts GF, Kremensky I, Kalaydjieva L. NDRG1 interacts von Deimling A, Platten M, Weller M, Wick W. NDRG1 with APO A-I and A-II and is a functional candidate for the prognosticates the natural course of disease in WHO grade HDL-C QTL on 8q24. Biochem Biophys Res Commun. 2005 II glioma. J Neurooncol. 2014 Mar;117(1):25-32 Jul 15;332(4):982-92 Hunter M, Bernard R, Freitas E, Boyer A, Morar B, Martins IJ, Tournev I, Jordanova A, Guergelcheva V, Ishpekova B,

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 418

NDRG1 (N-myc downstream regulated 1) Nagai MA, Mangone FR

Kremensky I, Nicholson G, Schlotter B, Lochmüller H, Voit Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, T, Colomer J, Thomas PK, Levy N, Kalaydjieva L. Mutation Kage M, Aoyagi S, Kinoshita H, Kuwano M.. Tumor growth screening of the N-myc downstream-regulated gene 1 suppression in pancreatic cancer by a putative metastasis (NDRG1) in patients with Charcot-Marie-Tooth Disease. suppressor gene Cap43/NDRG1/Drg-1 through modulation Hum Mutat. 2003 Aug;22(2):129-35 of angiogenesis. Cancer Res. 2006 Jun 15;66(12):6233-42. Huynh JL, Garg P, Thin TH, Yoo S, Dutta R, Trapp BD, Masuda K, Ono M, Okamoto M, Morikawa W, Otsubo M, Haroutunian V, Zhu J, Donovan MJ, Sharp AJ, Casaccia P. Migita T, Tsuneyoshi M, Okuda H, Shuin T, Naito S, Epigenome-wide differences in pathology-free regions of Kuwano M.. Downregulation of Cap43 gene by von Hippel- multiple sclerosis-affected brains. Nat Neurosci. 2014 Lindau tumor suppressor protein in human renal cancer Jan;17(1):121-30 cells. Int J Cancer. 2003 Jul 20;105(6):803-10. Kachhap SK, Faith D, Qian DZ, Shabbeer S, Galloway NL, Murakami Y, Hosoi F, Izumi H, Maruyama Y, Ureshino H, Pili R, Denmeade SR, DeMarzo AM, Carducci MA. The N- Watari K, Kohno K, Kuwano M, Ono M. Identification of sites Myc down regulated Gene1 (NDRG1) Is a Rab4a effector subjected to serine/threonine phosphorylation by SGK1 involved in vesicular recycling of E-cadherin. PLoS One. affecting N-myc downstream-regulated gene 1 2007 Sep 5;2(9):e844 (NDRG1)/Cap43-dependent suppression of angiogenic CXC chemokine expression in human pancreatic cancer Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, cells Biochem Biophys Res Commun 2010 May de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, 28;396(2):376-81 Worsley P, Rosenthal A, King RH, Thomas PK. N-myc downstream-regulated gene 1 is mutated in hereditary Nagai MA, Gerhard R, Fregnani JH, Nonogaki S, Rierger motor and sensory neuropathy-Lom. Am J Hum Genet. RB, Netto MM, Soares FA. Prognostic value of NDRG1 and 2000 Jul;67(1):47-58 SPARC protein expression in breast cancer patients Breast Cancer Res Treat 2011 Feb;126(1):1-14 Kim KT, Ongusaha PP, Hong YK, Kurdistani SK, Nakamura M, Lu KP, Lee SW. Function of Drg1/Rit42 in p53- Nishie A, Masuda K, Otsubo M, Migita T, Tsuneyoshi M, dependent mitotic spindle checkpoint. J Biol Chem. 2004 Kohno K, Shuin T, Naito S, Ono M, Kuwano M. High Sep 10;279(37):38597-602 expression of the Cap43 gene in infiltrating macrophages of human renal cell carcinomas Clin Cancer Res 2001 Kokame K, Kato H, Miyata T. Homocysteine-respondent Jul;7(7):2145-51 genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes. J Biol Chem. Okamoto Y, Goksungur MT, Pehlivan D, Beck CR, 1996 Nov 22;271(47):29659-65 Gonzaga-Jauregui C, Muzny DM, Atik MM, Carvalho CM, Matur Z, Bayraktar S, Boone PM, Akyuz K, Gibbs RA, Kovacevic Z, Chikhani S, Lui GY, Sivagurunathan S, Battaloglu E, Parman Y, Lupski JR. Exonic duplication CNV Richardson DR. The iron-regulated metastasis suppressor of NDRG1 associated with autosomal-recessive HMSN- NDRG1 targets NEDD4L, PTEN, and SMAD4 and inhibits Lom/CMT4D Genet Med 2014 May;16(5):386-94 the PI3K and Ras signaling pathways. Antioxid Redox Signal. 2013 Mar 10;18(8):874-87 Okuda T, Higashi Y, Kokame K, Tanaka C, Kondoh H, Miyata T.. Ndrg1-deficient mice exhibit a progressive Krauter-Canham R, Bronner R, Evrard JL, Hahne G, Friedt demyelinating disorder of peripheral nerves. Mol Cell Biol. W, Steinmetz A.. A transmitting tissue- and pollen- 2004 May;24(9):3949-56. expressed protein from sunflower with sequence similarity to the human RTP protein. Plant Sci. 1997; 129: 191-202. Piquemal D, Joulia D, Balaguer P, Basset A, Marti J, Commes T.. Differential expression of the RTP/Drg1/Ndr1 Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson gene product in proliferating and growth arrested cells. SA, Lee SW.. Inhibition of tumor cell growth by RTP/rit42 Biochim Biophys Acta. 1999 Jul 8;1450(3):364-73. and its responsiveness to p53 and DNA damage. Cancer Res. 1998 Oct 1;58(19):4439-44. Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F.. Characterization and expression of three novel Lachat P, Shaw P, Gebhard S, van Belzen N, Chaubert P, differentiation-related genes belong to the human NDRG Bosman FT.. Expression of NDRG1, a differentiation- gene family. Mol Cell Biochem. 2002 Jan;229(1-2):35-44. related gene, in human tissues. Histochem Cell Biol. 2002 Nov;118(5):399-408. Epub 2002 Oct 10. Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV.. The regulation of hypoxic genes Lee JE, Kim JH. SUMO modification regulates the protein by calcium involves c-Jun/AP-1, which cooperates with stability of NDRG1 Biochem Biophys Res Commun 2015 hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Mar 27;459(1):161-5 Biol. 2002 Mar;22(6):1734-41. Leth-Larsen R, Lund R, Hansen HV, Laenkholm AV, Tarin Shah MA, Kemeny N, Hummer A, Drobnjak M, Motwani M, D, Jensen ON, Ditzel HJ. Metastasis-related plasma Cordon-Cardo C, Gonen M, Schwartz GK.. Drg1 membrane proteins of human breast cancer cells identified by comparative quantitative mass spectrometry Mol Cell expression in 131 colorectal liver metastases: correlation Proteomics 2009 Jun;8(6):1436-49 with clinical variables and patient outcomes. Clin Cancer Res. 2005 May 1;11(9):3296-302. Li J, Kretzner L.. The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell Shimono A, Okuda T, Kondoh H.. N-myc-dependent types with overexpressed N- or c-myc. Mol Cell Biochem. repression of ndr1, a gene identified by direct subtraction of 2003 Aug;250(1-2):91-105. whole mouse embryo cDNAs between wild type and N-myc mutant. Mech Dev. 1999 May;83(1-2):39-52. Li Y, Pan P, Qiao P, Liu R. Downregulation of N-myc downstream regulated gene 1 caused by the methylation of Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, CpG islands of NDRG1 promoter promotes proliferation and Jackson RS 2nd, Wang M, Liang P.. NDRG1 is necessary invasion of prostate cancer cells Int J Oncol 2015 for p53-dependent apoptosis. J Biol Chem. 2004 Nov Sep;47(3):1001-8 19;279(47):48930-40. Epub 2004 Sep 17.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 419

NDRG1 (N-myc downstream regulated 1) Nagai MA, Mangone FR

Strzelczyk B, Szulc A, Rzepko R, Kitowska A, Skokowski J, Unoki M, Nakamura Y.. Growth-suppressive effects of Szutowicz A, Pawelczyk T. Identification of high-risk stage BPOZ and EGR2, two genes involved in the PTEN signaling II colorectal tumors by combined analysis of the NDRG1 pathway. Oncogene. 2001 Jul 27;20(33):4457-65. gene expression and the depth of tumor invasion Ann Surg Oncol 2009 May;16(5):1287-94 Zhou D, Salnikow K, Costa M.. Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res. 1998 Sugiki T, Murakami M, Taketomi Y, Kikuchi-Yanoshita R, May 15;58(10):2182-9. Kudo I.. N-myc downregulated gene 1 is a phosphorylated protein in mast cells. Biol Pharm Bull. 2004 May;27(5):624- Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, 7. Miyata T. Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically Sun J, Zhang D, Bae DH, Sahni S, Jansson P, Zheng Y, expressed in brain and heart Genomics 2001 Apr Zhao Q, Yue F, Zheng M, Kovacevic Z, Richardson DR. 1;73(1):86-97 Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors Zoroddu MA, Kowalik-Jankowska T, Kozlowski H, Salnikow Carcinogenesis 2013 Sep;34(9):1943-54 K, Costa M. Ni(II) and Cu(II) binding with a 14-aminoacid sequence of Cap43 protein, TRSRSHTSEGTRSR J Inorg Taketomi Y, Sugiki T, Saito T, Ishii S, Hisada M, Suzuki- Biochem 2001 Mar;84(1-2):47-54 Nishimura T, Uchida MK, Moon TC, Chang HW, Natori Y, Miyazawa S, Kikuchi-Yanoshita R, Murakami M, Kudo I.. van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van Identification of NDRG1 as an early inducible gene during in der Made AC, Nozawa Y, Vlietstra R, Trapman J, Bosman vitro maturation of cultured mast cells. Biochem Biophys FT.. A novel gene which is up-regulated during colon Res Commun. 2003 Jun 27;306(2):339-46. epithelial cell differentiation and down-regulated in colorectal neoplasms. Lab Invest. 1997 Jul;77(1):85-92. Ulrix W, Swinnen JV, Heyns W, Verhoeven G. The differentiation-related gene 1, Drg1, is markedly This article should be referenced as such: upregulated by androgens in LNCaP prostatic adenocarcinoma cells FEBS Lett 1999 Jul 16;455(1-2):23- Nagai MA, Mangone FR. NDRG1 (N-myc downstream 6 regulated 1). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7):413-420.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 420 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

CYB5A (Cytochrome B5 Type A (microsomal)) Valentina E Gomez, Amir Avan, Godefridus J Peters, Elisa Giovannetti Department of Medical Oncology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.(VEG, GJP, EG) [email protected]; [email protected]; Molecular Medicine group, Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (AA) [email protected]; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa , Italy (EG) [email protected]

Published in Atlas Database: November 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/CYB5AID53723ch18q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66058/11-2015-CYB5AID53723ch18q22.pdf DOI: 10.4267/2042/66058

-FAUP1 (FBR-MuSV-Associated Ubiquitously Abstract Expressed (fox derived) Pseudogene 1; 18q22.3 Review on Cytochrome B5 Type A, with data on DNA/RNA DNA/RNA, on the protein encoded and the diseases in which the gene has been implicated. Description The CYB5A gene is situated on chromosome 18, Identity starting from 74250847 and ending at 74292016 bp. The gene encodes a membrane-bound cytochrome Other names: MCB5, CYB5 protein. HGNC (Hugo): CYB5A Transcription Location: 18q22.3 For this gene, seven alternatively spliced transcript Local order variants have been identified (CYB5A-001, -002, - Based on MapViewer, genes flanking are: 003, -004, -005, -006 and -007). Variants -001, -002, -FBX015 (F-box protein 15); 18q22.3 -005 and -006 are transcripts encoding for a protein -TIMM21 (Translocase of Inner Mitochondrial containing 134, 98 and 124, respectively. The Membrane 21 Homolog (yeast); 18q22.3 remaining variants do not code for a protein product: -CYB5A; 18q22.3 Variant -007 is a processed transcript containing 4 -C18orf63 (Chromosome 18 Open Reading Frame exons, whereas variants -003 and -004 have retained 63); 18q22.3 introns.

Figure 1. Localization of CYB5A on chromosome 18, q22.3. CYB5A starts from 74250847 and ends at 74292016 bp.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 421 CYB5A (Cytochrome B5 Type A (microsomal)) Gomez VE, et al.

codon, thereby producing a truncated protein of 45 Protein amino acid residues. Genomic DNA analysis Description revealed an AG-to-GC modification in the consensus 3' splicing junction of intron 1. The presence of this CYB5A belongs to the cytochrome b5 family of modification renders the splicing machinery to make electron transport proteins found in yeasts, plants use of the nearest AG in exon 2 as an alternative and animals. As a product of alternative splicing, the splice site, resulting in a 16-bp deletion in the CYB5A gene encodes three distinct protein mRNA. isoforms; the 134 amino acid membrane-bound form with a predicted molecular weight of 15,3 kDa, the Somatic 98 amino acid cytoplasmic form with 11,3 kDa and Additionally, a survey in the COSMIC mutation a 98 residues isoform from which experimental database (accession date: 6 November 6, 2015) confirmation is lacking. The membrane-bound revealed a total of 24 mutations present in different protein is composed of a single polypeptide chain human tumors. folded into two domains which are structurally independent. A non-polar fragment, able to anchor the polypeptide chain to the membrane and a polar, heme-binding fragment with catalytic activity. Expression The expression of cytochrome B type A seems to be highly regulated in some mammals. In rats with hypothyroidism, for instance, increased CYB5A levels have been found. Furthermore, a compound called propylthiouracil, which was used to treat hyperthyroidism triggered a similar effect, leading to a 50% increase in cytochrome B type A levels. Huang and colleagues studied the transcriptional regulation of human adrenal NClH295A cells and found that it was regulated by Sp3, SF1, GATA-6 and NF-1C, four of the five factors which also exert regulating effects on P450c17. Function Cytochrome B5 Type A is a hemoprotein which serves as an electron carrier in various biochemical reactions. Its most important function is the NADPH-dependent reduction of methemoglobin to ferrous hemoglobin, a factor required for stearyl- CoA-desaturase activity. Morevoer, cytochrome B5 Type A participates in fatty acid desaturation, sterol metabolism and cytochrome P450-catalyzed reactions. Homology The CYB5A gene is conserved in Rhesus monkey, chimpanzee, cow, dog, rat, mouse, chicken, frog, mosquito, fruit fly, C. elegans, rice and A. thaliana. Mutations Germinal A homozygous splice site mutation in the CYB5A gene in a patient with type IV hereditary methemoglobinemia was identified by Steggles and colleagues. The group isolated mRNA from reticulocytes and leukocytes from the patient and analyzed the CYB5A cDNA sequences by DNA sequencing. They found a 16-bp deletion in the cDNA which led to a new in-frame termination

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performed by the group revealed a novel role of CYB5A, namely, autophagy induction. Hepatocellular carcinoma (HCC) Lee and collaborators addressed a proteomic approach in order to identify novel biomarkers in resected tumor and adjacent non-malignant tissue samples of 80 HCC patients. This study revealed that CYB5A significantly correlated with serum AFP, a biomarker commonly used for HCC surveillance. Moreover they suggested that its decreased levels might be a result of the disruption of the membrane- bound polysome attachment, which is required for cytochrome b5 type A synthesis. Lung squamous cell carcinoma Sriram and colleagues analyzed 62 primary lung SCCs (28 with recurrence and 34 with no evidence of recurrence) using a whole-genome aCGH microarray to identify genomic copy number alterations specific to tumors. They identified Table 1. CYB5A mutations present in distinct types of CYB5A among prognostic genes that had lower tumors. The table includes the DNA modification (CDS copy number in the lung SCC of patients who Mutation), protein modification (AA Mutation), tissue and type of mutation (c.369C>T; c.45G>A; c.366C>T; recurred (Sriram et al., 2012). Moreover, they c.138T>C: Substitution-coding silent, c.339G>A: demonstrated association of the reduced copy Substitution-nonsense, c.245 246GG>TT: Complex, other: number and mRNA expression of SOCS6 with Substitution-missense). disease recurrence in SCC patients. Implicated in Ovarian cancer Cortesi et al., performed a comparative proteomic Breast cancer study on biopsies from six consecutive patients with The effects of cytochrome b5 on breast cancer endometrioid or serous ovarian carcinoma who had remain unclear. A proteomic approach addressed by not been previously treated with chemotherapy prior Neubauer and collaborators found differences in the to surgical resection, in order to recognize potential cytochrome b5 levels of sensitive to tamoxifen biomarkers. (ER+/PR+) and less sensitive (ER+/PR-) mammary They identified CYB5A among the proteins tumor specimens. The ER+/PR+ samples exhibited separated by 2-DE electrophoresis and detected by decreased levels of cytochrome b5 and this lead the MS analysis. group to suggest that the differential susceptibility against tamoxifen might, in part be explained, as a Colorectal tumors result of aberrant cytochrome b5-dependent Agostini and collaborators evaluated the value of ten metabolism. markers including CYB5A (D18S58) in 44 CRC patients, who underwent surgery using a multiplex Pancreatic cancer PCR assay for a rapid and proper classification of CYB5A has been recently identified as a prognostic tumor microsatellite instability (MSI)-H, MSI-L and factor for Pancreatic Cancer Adenocarcinoma MSS. They revealed that a complete panel of these (PDAC). Giovannetti and collaborators performed markers could allow the accurate evaluation of comparative genomic hybridization studies in tumor MSI status in CRC patients, supporting further resected patients and found a significant correlation investigations on the prognostic value of CYB5A between decreased survival and the loss of the and other markers in management of CRC patients. cytoband 18q22.3, where CYB5A is located. Analysis of mRNA and protein levels of other Gastric Cancer cohorts revealed the prognostic value of CYB5A: Nair and colleagues carried out gene expression decreased CYB5A expression levels were associated analysis in Singapore and UK Gastric cancer with shorter survival. In vivo orthotopic models with datasets using GeneSpring. This study showed the patient-derived CYB5A+ cells showed a significant upregulation of CYB5A in the Singapore's reduction in tumor size coupled with increased Population (Nair et al., 2014). survival compared to the controls. Interestingly, additional gain- and loss-of function studies

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Rheumatoid arthritis (RA) Applied Research Foundation (to VEG, GJP and EG) grants. RA is characterized by decreased androgens levels and CYB5A acts as a cofactor of one of the two enzymes responsible for de novo androgens References synthesis, cytochrome P450 17A1 (17,20-lyase). For Agostini M, Enzo MV, Morandi L, Bedin C, Pizzini S, Mason this reason, Stark and collaborators analyzed the S, Bertorelle R, Urso E, Mescoli C, Lise M, Pucciarelli S, presence of Single Nucleotide Polymorphisms Nitti D. A ten markers panel provides a more accurate and complete microsatellite instability analysis in mismatch (SNPs) in the CYB5A gene in two published RA repair-deficient colorectal tumors. Cancer Biomark. Genome Wide Association Study (GWAS) datasets. 2010;6(1):49-61 Subsequently, cytochrome b5 expression analyses as Bai Y, Zhang JB, Xue Y, Peng YL, Chen G, Fang MY. well as androgen production after steroid conversion Differential expression of CYB5A in Chinese and European were evaluated in candidate SNPs from a RA case- pig breeds due to genetic variations in the promoter region. control study. Among the most important findings Anim Genet. 2015 Feb;46(1):16-22 was the identification of a SNP in CYB5A, Gómez VE, Giovannetti E, Peters GJ. Unraveling the designated as rs1790834, which was associated to complexity of autophagy: Potential therapeutic applications decreased risk of RA. The group suggested that in Pancreatic Ductal Adenocarcinoma. Semin Cancer Biol. 2015 Dec;35:11-9 rs1790834 might exert its protective effects by increasing the capacity of androgen synthesis. Giordano SJ, Kaftory A, Steggles AW. A splicing mutation in the cytochrome b5 gene from a patient with congenital Type 2 diabetes and adiposity methemoglobinemia and pseudohermaphrodism. Hum Genet. 1994 May;93(5):568-70 Huang and colleagues performed whole exome sequencing in order to identify potential functional Huang K, Nair AK, Muller YL, Piaggi P, Bian L, Del Rosario coding variants affecting metabolic processes M, Knowler WC, Kobes S, Hanson RL, Bogardus C, Baier LJ. Whole exome sequencing identifies variation in CYB5A associated with increased risk of type 2 diabetes. and RNF10 associated with adiposity and type 2 diabetes. Their analyses revealed a SNP in CYB5A, Obesity (Silver Spring). 2014 Apr;22(4):984-8 designated as rs7238987, which was significantly Huang N, Dardis A, Miller WL. Regulation of cytochrome b5 associated with pre-diabetic traits such as Percentage gene transcription by Sp3, GATA-6, and steroidogenic Body Fat (PFAT) and Body Mass Index (BMI). All factor 1 in human adrenal NCI-H295A cells. Mol Endocrinol. together, the group identified a potential new locus 2005 Aug;19(8):2020-34 for adiposity and higher risk of type 2 diabetes. Idkowiak J, Randell T, Dhir V, Patel P, Shackleton CH, Nevertheless, functional studies validating these Taylor NF, Krone N, Arlt W. A missense mutation in the results are still lacking. human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency. J Cushing' Syndrome Clin Endocrinol Metab. 2012 Mar;97(3):E465-75 Ječmen T, Ptáčková R, Černá V, Dračínská H, Hodek P, The effects of cytochrome b5 on cytochrome P450 Stiborová M, Hudeček J, Šulc M. Photo-initiated 17A1 have been shown by distinct research groups. crosslinking extends mapping of the protein-protein Since Cushing's syndrome is characterized by interface to membrane-embedded portions of cytochromes abnormalities in the production of cortisol and P450 2B4 and b₅ . Methods. 2015 Nov 1;89:128-37 adrenal androgens, the expression levels and activity Kaderbhai MA, Morgan R, Kaderbhai NN. The membrane- of cytochrome b5 in this condition have also been interactive tail of cytochrome b(5) can function as a stop- evaluated. Sakai and colleagues performed in vitro transfer sequence in concert with a signal sequence to give inversion of protein topology in the endoplasmic reticulum. biochemical assays on adrenocortical adenoma Arch Biochem Biophys. 2003 Apr 15;412(2):259-66 tissue from Cushin's syndrome patients and found high levels of cytochrome b5, which correlated with Lee B, Lee HJ, Cho HY, Suh DH, Kim K, No JH, Kim H, Kim YB. Ataxia-Telangiectasia and RAD3-Related and Ataxia- higher 17,20-lyase activity. Moreover, an Telangiectasia-Mutated Proteins in Epithelial Ovarian immunohistochemical study performed by Yanase Carcinoma: Their Expression and Clinical Significance. and collaborators revealed high cytochrome b5 Anticancer Res. 2015 Jul;35(7):3909-16 levels in all adrenocortical layers in adrenal glands, Lee NP, Chen L, Lin MC, Tsang FH, Yeung C, Poon RT, with a particularly intense immunoreactivity in the Peng J, Leng X, Beretta L, Sun S, Day PJ, Luk JM. zona reticularis, providing evidence for the Proteomic expression signature distinguishes cancerous and nonmalignant tissues in hepatocellular carcinoma. J functional association between cytochrome b5 type Proteome Res. 2009 Mar;8(3):1293-303 A and the production of adrenal androgens. Neubauer H, Clare SE, Kurek R, Fehm T, Wallwiener D, Sotlar K, Nordheim A, Wozny W, Schwall GP, Poznanović To be noted S, Sastri C, Hunzinger C, Stegmann W, Schrattenholz A, Cahill MA. Breast cancer proteomics by laser capture This work was supported by the AIRC-Start-Up, microdissection, sample pooling, 54-cm IPG IEF, and Istituto Toscano Tumori (to EG) CCA Foundation differential iodine radioisotope detection. Electrophoresis. (#2012-5-07 to EG and GJP) and "The Law Offices 2006 May;27(9):1840-52 of Peter G. Angelos Grant" from the Mesothelioma

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CYB5A (Cytochrome B5 Type A (microsomal)) Gomez VE, et al.

Sakai Y, Yanase T, Hara T, Takayanagi R, Haji M, Nawata Yamamoto K, Gildenberg M, Ahuja S, Im SC, Pearcy P, H. In-vitro evidence for the regulation of 17,20-lyase activity Waskell L, Ramamoorthy A. Probing the transmembrane by cytochrome b5 in adrenocortical adenomas from patients structure and topology of microsomal cytochrome-p450 by with Cushing's syndrome. Clin Endocrinol (Oxf). 1994 solid-state NMR on temperature-resistant bicelles. Sci Rep. Feb;40(2):205-9 2013;3:2556 Sriram KB, Larsen JE, Savarimuthu Francis SM, Wright CM, Yanase T, Sasano H, Yubisui T, Sakai Y, Takayanagi R, Clarke BE, Duhig EE, Brown KM, Hayward NK, Yang IA, Nawata H. Immunohistochemical study of cytochrome b5 in Bowman RV, Fong KM. Array-comparative genomic human adrenal gland and in adrenocortical adenomas from hybridization reveals loss of SOCS6 is associated with poor patients with Cushing's syndrome. Endocr J. 1998 prognosis in primary lung squamous cell carcinoma. PLoS Feb;45(1):89-95 One. 2012;7(2):e30398 This article should be referenced as such: Stark K, Straub RH, Rovenský J, Blažičková S, Eiselt G, Schmidt M. CYB5A polymorphism increases androgens Gomez VE, Avan A, Peters GJ, Giovanetti E. CYB5A and reduces risk of rheumatoid arthritis in women. Arthritis (Cytochrome B5 Type A (microsomal)). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7):421-425.

Res Ther. 2015 Mar 11;17:56

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Leukaemia Section Short Communication der(20)t(1;20)(q10-21;q11-13) Adriana Zamecnikova, Soad Al Bahar Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait

Published in Atlas Database: June 2015 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0120q10q11ID1657.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66059/06-2015-t0120q10q11ID1657.pdf DOI: 10.4267/2042/66059 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Phenotype/cell stem origin Suggested involvement of a pluripotent stem cell. Review on t(1;20)(q10-21;q11-13), with data on Epidemiology clinics. Rare karyotypic event in various hematologic Clinics and pathology malignancies; AML/MDS (5 cases), ALL (4 cases), MPN (2 cases), MM (4 cases), lymphoma (4 cases). Disease Male predominance (15 males/ 3 females); patients Acute myeloid leukemia (AML), acute ages ranged from 1 to 73 years; described mainly in lymphoblastic leukemia (ALL), myeloproliferative adults (aged 28 to 73 years); all the 4 ALL patients neoplasm (MPN), Myelodysplastic syndrome were children (aged 1 to 7 years) (Table 1). (MDS), multiple myeloma (MM), Burkitt Prognosis lymphomas and non-Burkitt type lymphomas. Seems to confer a poor prognosis.

Sex Age Karyotype Diagnosis Reference 1 M 49 46,XY,t(3;11)(p13;q21)/46,XY,der(20)t(1;20)(q21;q13) biclonal clones PV Wan et al; 2001 2 F 46,XX,dup(1)(q21q25),dup(1)(q21q42),del(7)(q31),del(11)(q21q25),add(17) MDS Alter et al; (q25),der(20)t(1;20)(q10;q13) Fanconi 2000 46,XX,dup(1)(q21q42),del(7),del(11),der(20)t(1;20) anemia 3 M 38 47,XY,+?der(1)t(1;20)(q21;q11)del(1)(p11),-9,t(9;22)(q34;q11),+18,der(20)t CML Mori et al; (1;20)(q21;q11) 1997 4 M 30 46,XY,t(11;12)(q13;p13)/46,idem,der(9)t(1;9)(q12;p24)/ AML-M5 Itzhar et 46,idem,der(14)t(1;14)(q12;p10)/ al; 2011 46,idem,der(20)t(1;20)(q12;q13)/46,idem,der(21)t(1;21) (q12;q10) 5 F 46,XX,der(20)t(1;20)(q21;q13) AML Raimondi et al;1999 6 M 34 47,XY,t(9;22)(q34;q11),t(10;21)(p11;q22),der(20)t(1;20)(q21;q13),+der(22)t AML-M1 Sasaki et (9;22)/48,idem,+8 al; 1983 7 F 7 56,XX,+X,+X,t(2;16)(p12;q12),+4,+5,+6,+10,+18,der(20)t(1;20)(q12;q13),+21, ALL Busson- +21,+mar Le Coniat et al; 1999 8 M 56,XY,+X,+Y,+5,+6,i(7)(q10),+9,+10,+11,+18,der(20)t(1;20)(q12;q13),+21,+22 ALL Hereema et al; 2004 9 F 1 46,XX,t(4;11)(q21;q23),der(20)t(1;20)(q11;q13) ALL Prigogina et al; 1998

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 426 der(20)t(1;20)(q10-21;q11-13) Zamecnikova A, Al Bahar S

10 M 4 45,X,-Y,der(20)t(1;20)(q21;q13) B-ALL Raimondi et al; 2003 11 M 59 47,XY,der(16)t(1;16)(q21;q11),+der(19)t(1;19)(q21;q13),der(20)t(1;20) MM Keung et (q21;q11) al; 1999 12 M 73 42,X,-Y,del(1)(p13p22),der(1;7)t(1;7)(p13;?p22)ins(1;?)(p13;?),del(2)(q31q37), MM Mohamed dic(7;9)(p15;q34),-8,-9,der(10)t(8;10)(q11;p12),-13,add(15)(q26), der(20)t(1;20) et al; 2007 (q12;q13) 13 M 54 54,XY,+3,+5,+9,+9,+15,+15,del(18)(q22),+19,der(20)t(1;20)(q21;q13),+21 MM Mohamed et al; 2007 14 M 51-54,XY,+1,der(1;16)(q10;p10),+3,t(4;18)(p14;p11),del(6)(q25),del(6)(q23), MM Sawyer et +del(6)(q11),+7,+9,add(11)(q23),-13,+15,+18,der(20)t(1;20)(q12;q13),+mar al; 1998 15 F 28 46,XX,t(14;18)(q32;q21)/47,idem,+12/47,idem,t(5;7)(q22;q32),+12/47,idem,+12, FL B-cell Horsman der(20)t(1;20)(q21;q13) lymph node et al; 2001 16 M 2 47,XY,del(2)(q21q31),t(3;22)(q27;q11),del(6)(q13q15),der(8)t(2;8)(q21;q24), DLBCL Itoyama et +11,der(20)t(1;20)(q21;q13) lymph node al; 2002 17 M 73 46,XY,i(6)(p10),t(8;14)(q24;q32),der(20)t(1;20)(q21;q13) lymph node BL Lones et al; 2004 18 M 48,Y,t(X;1)(q28;p22),+Y,t(5;12;16)(p14;q24;p13),der(6)t(6;18)(q13;q21),-8, B-cell Shimazaki del(8)(p21),+add(9)(q22),add(12)(p11),der(18)t(8;18)(q11;q21),der(19)t(12;19) lymphoma et al; 1999 (p11;q13),del(20)(q13),der(20)t(1;20)(q21;q11),+mar lymph node Abbreviations: PV, Polycythemia vera; MDS, myelodysplastic syndrome; CML, Chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; FL, follicular lymphoma, DLBCL, diffuse large B-cell lymphoma; BL, Burkitt lymphoma/leukemia; MM, multiple myeloma.

Cytogenetics Result of the chromosomal Cytogenetics morphological anomaly Cytogenetically heterogeneous, the breakpoints in Fusion protein 1q varied from 1q10 to 1q21, with a clustering to Oncogenesis 1q21, and the 20q breaks occurred in 20q10 to Unbalanced translocations involving all or part of 20q13, mainly in the 20q13 region. the long arms of chromosomes 1 and 20 are found in both hematologic neoplasms and lymphomas. The abnormality is usually present with complex pattern of rearrangements or occurring in a subclone; indicating that der(20)t(1;20) might be a secondary aberration. The extra copy of 1q segment and/ or 20q monosome may directly or indirectly provide a proliferative advantage leading to clonal evolution associated with tumor progression and advanced disease. References Alter BP, Caruso JP, Drachtman RA, Uchida T, Velagaleti GV, Elghetany MT. Fanconi anemia: myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet. 2000 Mar;117(2):125-31 Andreasson P, Johansson B, Billström R, Garwicz S, Mitelman F, Höglund M. Fluorescence in situ hybridization analyses of hematologic malignancies reveal frequent cytogenetically unrecognized 12p rearrangements. Partial karyotypes showing the unbalanced t(20)t(q10;q11). Leukemia. 1998 Mar;12(3):390-400 Additional anomalies Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, Usually present with additional chromosomal Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, abnormalities; may be found together with well- Berger R. Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: known primary abnormalities such as rearrangements of DNA satellite II and new recurrent t(9;22)(q34;q11), t(4;11)(q21;q23), and translocations. Leukemia. 1999 Dec;13(12):1975-81 t(14;18)(q32;q21), t(8;14)(q24;q32).

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der(20)t(1;20)(q10-21;q11-13) Zamecnikova A, Al Bahar S

Heerema NA, Nachman JB, Sather HN, La MK, Hutchinson chromosomal abnormalities in acute lymphoblastic R, Lange BJ, Bostrom B, Steinherz PG, Gaynon PS, Uckun leukemia of childhood. Cancer Genet Cytogenet. 1988 FM. Deletion of 7p or monosomy 7 in pediatric acute Jun;32(2):183-203 lymphoblastic leukemia is an adverse prognostic factor: a report from the Children's Cancer Group. Leukemia. 2004 Raimondi SC, Zhou Y, Mathew S, Shurtleff SA, Sandlund May;18(5):939-47 JT, Rivera GK, Behm FG, Pui CH. Reassessment of the prognostic significance of hypodiploidy in pediatric patients Horsman DE, Connors JM, Pantzar T, Gascoyne RD. with acute lymphoblastic leukemia. Cancer. 2003 Dec Analysis of secondary chromosomal alterations in 165 15;98(12):2715-22 cases of follicular lymphoma with t(14;18). Genes Chromosomes Cancer. 2001 Apr;30(4):375-82 Sasaki M, Kondo K, Tomiyasu T. Cytogenetic characterization of ten cases of Ph1-positive acute Itoyama T, Nanjungud G, Chen W, Dyomin VG, Teruya- myelogenous leukemia. Cancer Genet Cytogenet. 1983 Feldstein J, Jhanwar SC, Zelenetz AD, Chaganti RS. Jun;9(2):119-28 Molecular cytogenetic analysis of genomic instability at the 1q12-22 chromosomal site in B-cell non-Hodgkin Sawyer JR, Lukacs JL, Munshi N, Desikan KR, Singhal S, lymphoma. Genes Chromosomes Cancer. 2002 Mehta J, Siegel D, Shaughnessy J, Barlogie B. Identification Dec;35(4):318-28 of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping. Blood. 1998 Dec Itzhar N, Dessen P, Toujani S, Auger N, Preudhomme C, 1;92(11):4269-78 Richon C, Lazar V, Saada V, Bennaceur A, Bourhis JH, de Botton S, Bernheim A. Chromosomal minimal critical Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, regions in therapy-related leukemia appear different from Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, those of de novo leukemia by high-resolution aCGH. PLoS Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee One. 2011 Feb 14;6(2):e16623 F, Barlogie B. Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in Keung YK, Balogun OA, Tonk V. "Jumping translocation" cytogenetically defined high-risk disease. Blood. 2014 Apr and multiple myeloma. Cancer Genet Cytogenet. 1999 Jul 17;123(16):2504-12 1;112(1):60-1 Shimazaki C, Inaba T, Shimura K, Okamoto A, Takahashi Lones MA, Sanger WG, Le Beau MM, Heerema NA, Sposto R, Hirai H, Sudo Y, Ashihara E, Adachi Y, Murakami S, R, Perkins SL, Buckley J, Kadin ME, Kjeldsberg CR, Saigo K, Fujita N, Nakagawa M. B-cell lymphoma Meadows A, Siegel S, Finlay J, Bergeron S, Cairo MS. associated with haemophagocytic syndrome: a clinical, Chromosome abnormalities may correlate with prognosis in immunological and cytogenetic study. Br J Haematol. 1999 Burkitt/Burkitt-like lymphomas of children and adolescents: Mar;104(4):672-9 a report from Children's Cancer Group Study CCG-E08. J Pediatr Hematol Oncol. 2004 Mar;26(3):169-78 Smadja NV, Fruchart C, Isnard F, Louvet C, Dutel JL, Cheron N, Grange MJ, Monconduit M, Bastard C. Mohamed AN, Bentley G, Bonnett ML, Zonder J, Al-Katib A. Chromosomal analysis in multiple myeloma: cytogenetic Chromosome aberrations in a series of 120 multiple evidence of two different diseases Leukemia 1998 myeloma cases with abnormal karyotypes. Am J Hematol. Jun;12(6):960-9 2007 Dec;82(12):1080-7 Smadja NV, Leroux D, Soulier J, Dumont S, Arnould C, Mori N, Morosetti R, Lee S, Spira S, Ben-Yehuda D, Schiller Taviaux S, Taillemite JL, Bastard C. Further cytogenetic G, Landolfi R, Mizoguchi H, Koeffler HP. Allelotype analysis characterization of multiple myeloma confirms that 14q32 in the evolution of chronic myelocytic leukemia. Blood. 1997 translocations are a very rare event in hyperdiploid cases Sep 1;90(5):2010-4 Genes Chromosomes Cancer 2003 Nov;38(3):234-9 Pedersen B, Nørgaard JM, Pedersen BB, Clausen N, Wan TS, Ma SK, Ho MY, Chan LC, Yip SF, Wong LG, Rasmussen IH, Thorling K. Many unbalanced Yeung YM. Cytogenetic biclonality in polycythemia vera: translocations show duplication of a translocation unusual and unrelated clones Cancer Genet Cytogenet participant. Clinical and cytogenetic implications in myeloid 2001 Nov;131(1):86-9 hematologic malignancies. Am J Hematol. 2000 Jul;64(3):161-9 This article should be referenced as such: Prigogina EL, Puchkova GP, Mayakova SA. Nonrandom Zamecnikova A, al Bahar S. der(20)t(1;20)(q10-21;q11- 13). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7):426-428.

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Leukaemia Section Short Communication t(1;19)(p13;p13.1) Adriana Zamecnikova, Soad Al Bahar Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait

Published in Atlas Database: June 2015 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0119p13p13ID1230.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66060/06-2015-t0119p13p13ID1230.pdf DOI: 10.4267/2042/66060

This article is an update of : Huret JL. t(1;19)(p13;p13.1). Atlas Genet Cytogenet Oncol Haematol 2002;6(3)

2002) and a 36 year-old male patient with AML-M1 Abstract (Ma et al; 2000), one 77-year-old female patient with post-polycythemic myelofibrosis (Suh et al; 2009) Review on t(1;19)(p13;p13.1), with data on clinics. and 2 myelodysplastic syndrome (MDS) patients with refractory anemia with ringed sideroblasts Clinics and pathology (RARS): a 21 year-old female with a suspicion of Disease Fanconi anemia 11 years before diagnosis of RARS (Tchinda et al; 2002) and a 60 year-old female Myeloid malignancies. patient (Suh et al; 2009). Epidemiology Prognosis Only 5 cases to date. Limited data; death occurred 8 months after Clinics diagnosis in the case with AML of infant (Tchinda et 2 patients with acute myeloid leukemia (AML): a 1 al; 2002); prognosis may be variable (chronic vs year-old infant with M5a AML (Tchinda et al; acute disease).

Sex Age Chromosomal anomalies Diagnosis Reference

1 M 36 40-46,XY,+der(1)t(1;19)(p13;p13.1) AML-M1 Ma et al; 2000

2 F 1 47,XX,+der(1)t(1;19)(p13;p13.1),der(10)inv(10)(p2?5q25) AML- M5a Tchinda et al; 2002

t(10;11)(q25;q25),der(11)t(10;11)

3 F 21 47,XX,+der(1)t(1;19)(p13;p13.1) MDS Tchinda et al; 2002

4 F 60 47,XX,+der(1)t(1;19)(p13;p13.1) MDS Suh et al; 2009

5 F 77 47,XX,+der(1)t(1;19)(p13;p13.1) Post PV-MF Suh et al; 2009

Table 1. Reported patients with der(1)t(1;19)(p13;p13.1). Abbreviations: F, female; M, male; AML, Acute myeloid leukemia; MDS, myelodysplastic syndrome; post PV-MF, post polycytemic myelofibrosis

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(7) 429 t(1;19)(p13;p13.1) Zamecnikova A, Al Bahar S

Cytogenetics in at least some cases. ELL is the MLL partner gene in t(11;19)(q23;p13.1) Cytogenetics morphological translocation resulting in MLL-ELL fusion that is The translocation presents as + der(1) found exclusively in patients with myeloid t(1;19)(p13;p13) in all the 5 known cases. malignancies. Similar to t(11;19)(q23;p13.1), the unbalanced der(1)t(1;19)(p13;p13.1) may constitute Additional anomalies a specific entity in myeloid neoplasms, occurring Sole anomaly in 4 of the 5 cases; complex anomalies mainly in adults. in an infant patient with AML-M5a. References Genes involved and Ma SK, Wan TS, Chan LC, Chiu EK. Hand-mirror blasts, proteins AML-M1, and der(1)t(1;19)-(p13;p13.1) Leuk Res. 2000 Jan;24(1):95-6 Note Suh B, Park TS, Song J, Lee ST, Kim SJ, Lee HW, Choi JR. The unbalanced rearrangement described as der(1)t(1;19)(p13;p13.1) in two elderly patients with myeloid der(1)t(1;19)(p13;p13.1) has rarely been reported, neoplasms: new case reports and review of the literature. may be found in sporadic cases of patients with Leuk Res. 2009 Aug;33(8):e128-31 myeloid neoplasms such as AML, MDS and Tchinda J, Volpert S, Neumann T, Kennerknecht I, Ritter J, polycythemia vera (PV). The possible role of such Büchner T, Berdel WE, Horst J. Novel der(1)t(1;19) in two patients with myeloid neoplasias. Cancer Genet Cytogenet. unbalanced translocation in disease pathogenesis 2002 Feb;133(1):61-5 needs to be determined and the genes implicated in this rearrangement still remain unknown. While no This article should be referenced as such: gene rearrangements were detected in this Zamecnikova A, al Bahar S. t(1;19)(p13;p13.1). Atlas translocation, it is possible that ELL, the gene Genet Cytogenet Oncol Haematol. 2016; 20(7):429-430. located on chromosome 19p13.1, may be involved

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