Number 2 February 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Volume 1 - Number 1 May - September 1997

Volume 21 - Number 2 February 2017 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).

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

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology

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

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. 2017; 21(2) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 21, Number 2, February 2017

Table of contents

Gene Section

SLC24A5 (solute carrier family 24 (sodium/potassium/calcium exchanger), member 5) 33 Kunal Ray, Mainak Sengupta, Sampurna Ghosh IRS2 (insulin receptor substrate 2) 35 João Agostinho Machado-Neto, Paula de Melo Campos, Fabiola Traina HNF4A (Hepatocyte Nuclear Factor 4 alpha) 44 Sinem Tunçer, Sreeparna Banerjee

Leukaemia Section t(8;21)(q22;q22) RUNX1/RUNX1T1 52 Wilma Kroes, Marian Stevens-Kroef t(8;14)(q24;q32) / t(2;8)(p12;q24) / t(8;22)(q24;q11) 56 Eva van den Berg, Marian Stevens-Kroef Anaplastic large cell lymphoma, ALK-negative 60 Rebecca L Boddicker, Andrew L Feldman Pediatric-type Follicular Lymphoma 64 Michael G. Ozawa, Robert S. Ohgami Plasmablastic lymphoma (PBL) 67 Aurelia Meloni-Ehrig, Lawrence Hertzberg Nodular sclerosis classical Hodgkin lymphoma (NScHL) 71 Antonino Carbone, Annunziata Gloghini

Cancer Prone Disease Section

Mulibrey nanism 76 Maria Piccione, Emanuela Salzano

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Short Communication

SLC24A5 (solute carrier family 24 (sodium/potassium/calcium exchanger), member 5) Kunal Ray, Mainak Sengupta, Sampurna Ghosh Academy of Scientific and Innovative Research (AcSIR), Campus at CSIR - Central Road Research Institute, Mathura Road, New Delhi - 110 025, [email protected] (KR); University of Calcutta, Department of Genetics, 35, Ballygunge Circular Road, Kolkata - 700 019, [email protected]); [email protected] (MS, SG) India.

Published in Atlas Database: April 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC24A5ID73332ch15q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68155/04-2016-SLC24A5ID73332ch15q21.pdf DOI: 10.4267/2042/68155 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 Transcription SLC24A5 is a member of the potassium-dependent This gene has 5 transcripts: 4 splice variants and 1 sodium/calcium exchanger family and encodes an unspliced form intracellular membrane protein. Sequence variations (http://www.ncbi.nlm.nih.gov/IEB/Research/Acem in this gene have been associated with differences in bly/av.cgi?db=humanc=Genel=SLC24A5). skin pigmentation, and the defective protein leads to The full protein coding transcript is 1617 bp long. Oculocutaneous albinism type VI, OCA6. Protein Keywords: OCA6, albinism, SLC24A5 Description Identity The gene encodes a cation exchanger which is 500 Other names: NCKX5, JSX, SHEP4, OCA6 amino acids protein of molecular mass 54888 Da; HGNC (Hugo): SLC24A5 this multi-pass membrane protein is an intracellular potassium-dependent sodium/calcium exchanger Location: 15q21.1 with 2 large hydrophilic loops and 2 sets of multiple trans-membrane-spanning segments. DNA/RNA The first large hydrophilic loop is located Description extracellularly at the N-terminus while the other is In Chromosome 15, the 21,701 bases long gene starts cytoplasmic and separates the two sets of from 48,120,972 bp from pter and ends at transmembrane domains. 48,142,672 bp from pter; Orientation: Plus strand. It It belongs to sodium/potassium/calcium exchanger contains 9 exons. family, SLC24A subfamily.

Cytogenetic band showing SLC24A5 locus (Ref: http://www.genecards.org/cgi- bin/carddisp.pl?gene=SLC24A5&keywords=SLC24A5)

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 33 SLC24A5 (solute carrier family 24 (sodium/potassium/calcium Ray K, et al. exchanger), member 5)

Expression nystagmus, foveal hypoplasia and reduced visual acuity. In a man from eastern India who had extreme Due to its localization in the melanosomal hypopigmentation resulting in pinkish-white skin, membrane, SLC24A5 is thought to be expressed in but with dark brown hair and brown irises, was found the melanocytes (Wilson S et al., 2013). to have a 4-bp insertion in the SLC24A5 gene as Interestingly, the expression of the gene in the homozygous genotype (Mondal et al, 2012). following tissue types are evident by its existence in the corresponding cDNA libraries: B-cell, brain, Somatic cerebellum, cerebrum, colon, embryonic tissue, Somatic variations in SLC24A5 have been identified fetus, gastrointestinal tract, kidney, liver, lung, in cancers lymph node, lymphoreticular, mammary gland, (https://dcc.icgc.org/mutations/MU45848787; nervous, pancreas, pancreatic islet, placenta, http://cancer.sanger.ac.uk/cosmic/search?q=SLC24 prostate, skin, stem cell, stomach, testis, thymus, A5), but no causality have been reported. uterus and vascular tissue (http://cgap.nci.nih.gov/Genes/GeneInfo?ORG=Hs References CID=710240). Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton Localisation HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, SLC24A5 is expressed in the trans-Golgi network of Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, melanocytes (Wilson S et al., 2013). Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC. SLC24A5, a putative cation Function exchanger, affects pigmentation in zebrafish and humans. The precise function of SLC24A5 is not yet known. Science. 2005 Dec 16;310(5755):1782-6 However, the potential functions include: (a) Mondal M, Sengupta M, Samanta S, Sil A, Ray K. Molecular transporting 1 Ca2+ and 1 K+ to the melanosome in basis of albinism in India: evaluation of seven potential exchange for 4 cytoplasmic Na (Lamason RL et al., candidate genes and some new findings. Gene. 2012 Dec 2005); (b) Influencing natural variation in skin 15;511(2):470-4 pigmentation via an unknown mechanism affecting Morice-Picard F, Lasseaux E, François S, Simon D, cellular sterol levels (Wilson S et al., 2013). Rooryck C, Bieth E, Colin E, Bonneau D, Journel H, Walraedt S, Leroy BP, Meire F, Lacombe D, Arveiler B. Homology SLC24A5 mutations are associated with non-syndromic oculocutaneous albinism. J Invest Dermatol. 2014 It belongs to Solute Carrier Family 24 Feb;134(2):568-571 (http://www.guidetopharmacology.org/GRAC/Fami Wei AH, Zang DJ, Zhang Z, Liu XZ, He X, Yang L, Wang Y, lyDisplayForward?familyId=202). Zhou ZY, Zhang MR, Dai LL, Yang XM, Li W. Exome sequencing identifies SLC24A5 as a candidate gene for Mutations nonsyndromic oculocutaneous albinism. J Invest Dermatol. 2013 Jul;133(7):1834-40 Germinal Wilson S, Ginger RS, Dadd T, Gunn D, Lim FL, Sawicka M, SLC24A5 mutations are responsible for Sandel M, Schnetkamp PP, Green MR. NCKX5, a natural regulator of human skin colour variation, regulates the Oculocutaneous Albinism type 6 (OCA6). Only 9 expression of key pigment genes MC1R and alpha-MSH SLC24A5 mutations have been reported till date - and alters cholesterol homeostasis in normal human one patient from India, one from China, two from melanocytes. Adv Exp Med Biol. 2013;961:95-107 France, three from Portugal, one from Belgium and one from Syria (Mondal et al. 2012; Wei et al., 2013; This article should be referenced as such: Fanny et al., 2014). Patients are generally Ray K, Sengupta M, Ghosh S. SLC24A5 (solute carrier characterized by light hair at birth that darkens with family 24 (sodium/potassium/calcium exchanger), member 5). Atlas Genet Cytogenet Oncol Haematol. age, white skin, transparent irises, photophobia, 2017; 21(2):33-34.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 34 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

IRS2 (insulin receptor substrate 2) João Agostinho Machado-Neto, Paula de Melo Campos, Fabiola Traina Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, (JAMN, FT), Hematology and Hemotherapy Center, University of Campinas - UNICAMP, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, (PdMC) Brazil. [email protected], [email protected], [email protected]

Published in Atlas Database: May 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/IRS2ID40994ch13q34.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68156/05-2016-IRS2ID40994ch13q34.pdf DOI: 10.4267/2042/68156 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract DNA/RNA Insulin receptor substrate 2 (IRS2) belongs to the Description insulin receptor substrate protein family and was initially discovered as an alternative route for IRS2 was discovered as an alternative route from signaling mediated by the insulin receptor. signaling mediated by the insulin receptor in Irs1 Currently, IRS2 has been well-established to knockout mice (Patti, et al. 1995). The entire IRS2 mediate mitogenic and antiapoptotic signaling from gene is approximately 33.8 Kb (start: 109752698 and several important cellular receptors. In the last years, end: 109786568 bp; orientation: Minus strand) and many studies have indicated that IRS2 participates in contains 2 exons. The IRS2 cDNA contains 7 Kb. the regulation of important biological processes involved in cancer phenotype, including cell Protein proliferation, clonogenicity, metabolism and survival. The present review contains data on IRS2 Description DNA/RNA, protein encoded and function. IRS2 belongs to the insulin receptor substrate (IRS) Keywords: IRS2; mitogenic signaling; protein family, which is characterized by the antiapoptotic signaling presence of a pleckstrin homology (PH) domain and a phosphotyrosine binding (PTB) domain (Figure 1) Identity in their protein structure. The PH domain contributes to protein-protein binding and facilitates the Other names: IRS-2, 4PS recruitment of IRS proteins by cell membrane HGNC (Hugo): IRS2 receptors. Location : 13q34

Figure 1. Schematic structure of IRS2. The pleckstrin homology (PH) domain (purple), phosphotyrosine binding (PTB) domain (green) and kinase regulatory loop binding domain (KRLB) are illustrated in the Figure. Amino acid (aa) positions are indicated.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 35 IRS2 (insulin receptor substrate 2) Machado-Neto JA, et al.

Figure 2. Intracellular localization of IRS2 protein in the SET2 cell line. Confocal analysis of SET2 (leukemia) cell line displaying IRS2 (red) and DAPI (blue) staining; MERGE shows the overlapped images. Scale bar: 5μm, as indicated. Note the predominant cytoplasm localization of IRS2. Anti-IRS2 (sc-1555) was from Santa Cruz Biotechnology and DAPI (P-36931) was from Life Technologies (Carlsbad, CA, USA). Personal data.

The PTB domain contains multiple tyrosine sites for (canonical pathway). phosphorylation and is activated by cell receptors. IRS2 also activates signaling pathways through other Differently to other IRS family members, IRS2 has mechanisms (non-canonical pathways). a kinase regulatory loop binding domain (KRLB) For instance, angiotensin II stimulates the rapid that contributes to the recruitment to cellular phosphorylation of JAK2 tyrosine residues, receptor (Mardilovich, et al. 2009a). increasing its catalytic activity and JAK2 - IRS2 Expression association (Folli, et al. 1997; Saad, et al. 1996; Saad, et al. 1995). Ubiquitous. The IRS2 - JAK2 association has also been described Localisation in rat left ventricular cells after stimulation with angiotensin (Velloso, et al. 2006; Velloso, et al. IRS2 protein is predominantly found in the 1996), and in rat liver after stimulation with leptin cytoplasm (Figure 2). (Carvalheira, et al. 2003). Similarly, the mutant form Function of JAK2 (JAK2V617F), which is constitutively IRS2 is a 180 kDa adapter protein described in 1995 activated, leads to enhanced interaction between as being equivalent to the 4PS protein previously JAK2 and IRS2 in myeloid cells (de Melo Campos, identified as a substrate associated with the IL4 et al. 2016). The main signaling pathways stimulated receptor in myeloid cells (Patti, et al. 1995). IRS2 by IRS2 are shown in Figure 3. mediates mitogenic and antiapoptotic signaling from insulin receptor (INSR), insulin-like growth factor 1 Homology (IGF1R), erythropoietin receptor (EPOR), The N-terminus of IRS2 shares high homology with thrombopoietin receptor (MPL), vascular that of the other members of the IRS protein family. endothelial growth factor receptor VEGFR (KDR), IRS2 also has a high homology among different leptin LEP, growth hormone (GH), interleukins and species (Table 1). IFNα/ IFNB1/IFNG, playing an important role in the response to stimuli for cytokines and growth factors, Mutations influencing the proliferation and survival of normal and cancer cells (Argetsinger, et al. 1996; Recurrent mutations in the IRS2 gene are rare, and Dearth, et al. 2007; Gibson, et al. 2007; Johnston, et 88 substitution missense, 2 substitution nonsense, 38 al. 1995; Platanias, et al. 1996; Sun, et al. 1995; substitution synonymous, 1 insertion inframe, 3 Uddin, et al. 1995; Verdier, et al. 1997; White, et al. insertion frameshift, 4 deletions inframe and 3 1994; Yenush, et al. 1997). In addition, stimulation deletion frameshift mutations are reported in of the insulin receptor is known to result in IRS2 COSMIC (Catalogue of somatic mutations in cancer; association with the p85 subunit of PI3K and GRB2, http://cancer.sanger.ac.uk/cancergenome/projects/c activating proteins involved in the PI3K/AKT/ osmic). MTOR and MAPK pathways, respectively (Patti, et al. 1995; Velloso, et al. 2006)

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 36

IRS2 (insulin receptor substrate 2) Machado-Neto JA, et al.

Figure 3. IRS2 signaling pathway. IRS2 is recruited by its PH/PTB domains and phosphorylated in tyrosine residues by upstream tyrosine kinase receptors (e.g. insulin receptor [IR], insulin-like growth factor receptor [IGF1R]). Tyrosine phosphorylation of IRS2 triggers PI3K/AKT/mTOR and MAPK signaling activation (canonical pathway), regulating many biological processes, including cell proliferation, protein synthesis, survival and gene expression in specific human tissues. IRS2 is also activated by cytokine and hormone receptors (e.g. IL4, leptin, angiotensin), which additionally induce JAK2 stimulation and IRS2/JAK2 interaction, leading to STAT, PI3K/AKT/mTOR and MAPK signaling activation in rat and mouse tissues. Abbreviations: P, phosphorylation; PY, tyrosine phosphorylation. Figure was produced using Servier Medical Art (http://www.servier.com/Powerpoint-image-bank).

% Identity for: by multivariate analysis (Clark, et al. 2011). In breast Homo sapiens Symbol Protein DNA cancer cell lines, high IRS2 expression was IRS2 correlated with high breast tumor invasiveness (Porter, et al. 2013), and with increased survival and vs. P. troglodytes IRS2 96.9 97.7 cell invasion under hypoxia conditions vs. M. mulatta IRS2 97.4 95.9 (Mardilovich, et al. 2009b). Breast cancer IRS2- depleted cells, using specific anti-sense constructs, vs. C. lupus IRS2 88.8 87.4 presented reduced IGF1-mediated cell motility and vs. B. taurus IRS2 85.0 84.8 lower anchorage independent growth (Jackson, et al. vs. M. musculus Irs2 84.7 80.8 2001). In agreement, others studies demonstrated that IRS2 activation was required for IGF1-induced vs. R. norvegicus Irs2 85.7 81.5 cell motility of the human breast cell lines MCF-7 vs. G. gallus IRS2 73.7 74.4 (Ibrahim, et al. 2008; Zhang, et al. 2004) and T47D- YA(Byron, et al. 2006). Nagle and colleagues vs. X. tropicalis LOC100498409 59.4 57.1 (Nagle, et al. 2004), showed that mammary tumor vs. D. rerio Irs2 60.7 61.7 cells from IRS2 knockout mice were less invasive vs. D. rerio zgc:56306 58.9 56.5 and presented more prominent apoptotic response to growth factor deprivation compared to wild type Table 1. Comparative identity of human IRS2 with other mammary tumor cells. Using breast cancer cell lines, species (Source: http://www.ncbi.nlm.nih.gov/homologene) Morelli and colleagues (Morelli, et al. 2003) and Cui Implicated in and colleagues (Cui, et al. 2003) also observed that IRS2 could be a target of estrogen and progesterone Breast cancer receptors, respectively. Cui and colleagues (Cui, et Jackson and colleagues (Jackson, et al. 1998) al. 2006) demonstrated that EGF signaling was also observed that IRS2 is widely expressed in breast involved in IRS2 induction/activation at the mRNA cancer cell lines and primary breast cancer cells. In and protein levels via c-JUN/AP-1 stimulation, breast cancer patients, membrane localization of establishing cross-talk between IGF1R and EGFR IRS-2 was associated with reduced overall survival signaling. Furthermore, the authors demonstrated in

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IRS2 (insulin receptor substrate 2) Machado-Neto JA, et al.

their study that IRS2 silencing reduced EGF-induced dual IGF-1R/IR inhibitor BMS-754807. In addition, invasion and migration in the mammary the authors, using public available SNP array data on adenocarcinoma cell line MDA-MB-468 (Cui, et al. tumors, observed that the frequency of IRS2 copy 2006). Using the nontumorigenic mammary number gain (648 samples evaluated from four epithelial cell line MCF-10A and transgenic mice datasets) is higher in colorectal cancer compared to overexpressing human IRS2 by MMTV promoter, other tumor types (Huang, et al. 2015). Death and colleagues (Dearth, et al. 2006) Pancreatic cancer demonstrated the potential of malignant transformation of mammary cells by in vitro and in In the rat pancreas RINm5F cell line, Irs2, but not vivo IRS2 overexpression. Wu and colleagues (Wu, Irs1, phosphorylation was associated with IGF1 et al. 2010) observed that IRS2 silencing impaired stimulated DNA synthesis (Zhang, et al. 1998). breast cancer cell proliferation. In addition, they Kornmann and colleagues (Kornmann, et al. 1998) described that IGF1 induced nuclear translocation of reported that IRS2 mRNA and protein were IRS2 and NFKB, and promoted intranuclear expressed in human pancreatic cancer cell lines association between IRS2 and NFKB in MCF-7 and (ASPC-1 and COLO-357), and highly expressed in BT-20 breast cancer cells, establishing a cross-talk primary pancreatic cancer samples compared with between IGF1R and NFKB signaling. Slattery and normal pancreatic samples. IGF1 and IGF2 colleagues (Slattery, et al. 2007), using a cohort of enhanced cell growth, stimulated IRS2 tyrosine 1664 patients with breast cancer (1089 non-Hispanic phosphorylation and IRS2/PI3K association in white and 575 Hispanic) and 2054 controls (1328 ASPC-1 and COLO-357 cells (Kornmann, et al. non-Hispanic white and 726 Hispanic), found no 1998). In AsPC-1 cell line, IGF1R/IRS2 axis association between IRS2 G1057D (rs1805097) controlled the VEGF transcription, indicating that polymorphism and breast cancer development. In this axis is an important mediator for tumor contrast, Feigelson and colleagues (Feigelson, et al. angiogenesis (Neid, et al. 2004). 2008) observed an association between IRS2 Neuroblastoma polymorphisms rs4773082 (640 patients and 650 controls), rs2289046 (552 patients and 589 controls) In SH-SY5Y, a human neuroblastoma cell line and rs754204 (642 patients and 655 controls) and lacking IRS1, IGF1 stimulation leads to IGF1R breast cancer development. activation and IRS2 phosphorylation, and activates PI3K and MAPK signaling (Kim, et al. 1998; Kim, Colorectal cancer et al. 2004). IRS2 also protects SH-EP and SH- Slattery and colleagues (Slattery, et al. 2004), using SY5Y neuroblastoma cell lines from glucose- a cohort of 1001 patients with colon cancer and 1167 induced apoptosis by activation of PI3K/AKT and controls, and 766 patients with rectal cancer and 983 MAPK signaling (Kim, et al. 2009; Stohr, et al. controls, reported that IRS2 G1057D (rs1805097) 2011). heterozygote GD genotype significantly reduced the risk of colon, though not rectal, cancer. In contrast, Hepatocellular carcinoma Yukseloglu and colleagues (Yukseloglu, et al. 2014), Boissan and colleagues (Boissan, et al. 2005) observed no association between IRS2 G1057D reported an overexpression of IRS2 in murine (rs1805097) polymorphism and risk for disease in a models of hepatocarcinogenesis. IRS2 mRNA and group of 161 patients with colorectal cancer and 197 protein were found to be overexpressed in human controls. Gunter and colleagues (Gunter, et al. 2007) hepatoma cell lines and primary human observed no association of IRS2 polymorphisms hepatocellular carcinoma specimens (Boissan, et al. rs2241745 (754 patients and 765 controls) and 2005; Cantarini, et al. 2006). Of note, inhibition of rs2289046 (744 patients and 758 controls) with IRS2 by siRNA resulted in increased apoptosis in the advanced colorectal adenoma. IRS2 (rs2289046) GG hepatocellular carcinoma Hep3B cells. In the human genotype compared with AA plus AG genotypes was hepatoma SMMC-7721 cell line, IRS2 silencing found to have a protective factor for colorectal suppressed aflatoxin B1-induced PI3K/AKT and cancer risk in normal weight subjects (Karimi, et al. MAPK activation and cell migration (Ma, et al. 2013). Day and colleagues (Day, et al. 2013) 2012). Rashad and colleagues (Rashad, et al. 2014) described that IRS2 mRNA and protein levels were observed, in 334 patients and 426 controls, that the positively correlated with progression from normal D allele and the DD genotype of IRS2 G1057D through adenoma to carcinoma in colorectal cancer, (rs1805097) polymorphism were significantly and that deregulated IRS2 expression activated the associated with hepatocellular carcinoma risk. PI3K/AKT pathway and increased cell adhesion. Hematological malignancies Using FISH analysis, Huang and colleagues (Huang, et al. 2015) demonstrated that IRS2 amplification IRS2 expression was found to be downregulated in was a recurrent event and that IRS2 levels modulated myelodysplastic syndrome patients compared with the sensibility of colorectal cancer cell lines to the healthy donors (Machado-Neto, et al. 2012).

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IRS2 (insulin receptor substrate 2) Machado-Neto JA, et al.

Increased IRS2 expression and phosphorylation was Thyroid cancer observed during erythroid, granulocytic and In the FRTL-5 rat thyroid cell line, the "RET/PTC3 megakaryocytic differentiation in establish leukemia rearrangement" (inv(10)(q11q11) with NCOA4/ cell line models (Machado-Neto, et al. 2012). IRS2 RET rearrangement), a constitutively activated was found to be constitutively associated with JAK2 tyrosine kinase receptor that is frequent in papillary in the JAK2 V617F-mutated HEL cells, but not in the thyroid cancer, induces IRS2 upregulation, and JAK2 wild type U937 cells (de Melo Campos, et al. enhances IRS2/PI3K interaction and AKT activation 2016). In HEL cells, though not in U937 cells, IRS2 (Miyagi, et al. 2004). silencing reduced cell viability and increased Akker and colleagues (Akker, et al. 2014) observed apoptosis; these effects were enhanced when no association between IRS2 G1057D (rs1805097) combined with ruxolitinib, a selective JAK1/2 polymorphism and differentiated thyroid cancer inhibitor. In addition, CD34+ cells from JAK2V617F- development in a cohort of 93 differentiated thyroid mutated myeloproliferative neoplasm patients cancer patients and 111 healthy controls. presented increased IRS2 mRNA levels (de Melo Campos, et al. 2016). Savage and colleagues Mesothelioma (Savage, et al. 2015) described IRS2 mutations IRS2 was found to be highly expressed in pleural (S594W and H1328R) in three out of 22 chronic mesothelioma samples and associated with cell myeloid leukemia patients with tyrosine kinase motility in the H2461 cell line (Hoang, et al. 2004). inhibitors resistance. Expression of each of the two of the IRS2 mutations in Ba/F3 cells demonstrated Clear cell renal cell carcinoma transformation capacity in the absence of IL3 Using semi-quantitative PCR, Al-Sarraf and (Savage, et al. 2015). When co-expressed in Ba/F3 colleagues (Al-Sarraf, et al. 2007) investigated IRS1, cells with BCR-ABL1, these IRS2 mutants IRS2 and IRS5 mRNA expression in a cohort of 10 conferred varying degrees of reduced sensitivity to patients with clear cell renal carcinoma, comparing imatinib in vitro (Savage, et al. 2015). normal adjacent tissue with the respective tumor tissue for the analysis, and found an upregulation of Glioblastoma IRS2 and IRS5 mRNA in tumor samples (Al-Sarraf, In a study focused on PI3K/AKT-related gene et al. 2007). expression analysis in glioblastoma involving 103 patients, the IRS2 gene was amplified and Endometrial cancer overexpressed in 2 cases and IRS2 was also highly Cayan and colleagues (Cayan, et al. 2010) reported expressed in six cases with no demonstrated that IRS2 G1057D (rs1805097) polymorphism was amplification (Knobbe, et al. 2003). Xu and associated with the development of endometrial colleagues (Xu, et al. 2011) identified IRS2 as a cancer in a cohort of 44 patients with colon cancer target of MicroRNA-153 and suggested that and 101 controls. MicroRNA-153 suppressed PI3K/AKT signaling through IRS2 inhibition in the DBTRG-05MG Malignant peripheral nerve sheath human glioblastoma cell line. tumor Prostate cancer High expression of IRS2 was observed in malignant peripheral nerve sheath tumor compared to Szabolcs and colleagues (Szabolcs, et al. 2009) neurofibromas (Shaw, et al. 2012). reported a high expression of IRS2 in prostate cancer IRS2 expression was also associated with reduced cell lines and in primary human prostate cancer survival in malignant peripheral nerve sheath tumors samples, in which IRS2 was also correlated with using univariate analysis (Shaw, et al. 2012). MYC expression in prostate tumor samples. Ibuki et al. (Ibuki, et al. 2014) demonstrated an elevated Bladder cancer IRS2 expression by immunohistochemistry in Using cDNA microarray analysis, Zekri and prostate cancer biopsies when compared to normal colleagues (Zekri, et al. 2015) found IRS2 specimens. The in vitro treatment of LNCaP human upregulation among the genes differently expressed prostate cancer cells with NT157, a IRS1/2 inhibitor, identified in bladder cancer. resulted in increased apoptosis and decreased cell proliferation (Ibuki, et al. 2014). Huang and Lung cancer colleagues (Huang, et al. 2012) observed that IRS2 Park and colleagues (Park, et al. 2015) identified rs7986346 polymorphism was associated with IRS2 as a MIR146A (MicroRNA-146a) target and disease progression and impaired survival in prostate suggested that MicroRNA-146a might suppress lung cancer patients treated with androgen-deprivation. cancer progression by IRS2 inhibition. Melanoma In the MDA-MB-435 melanoma cell line, IRS2 signaling was identified as a key mediator of

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IRS2 (insulin receptor substrate 2) Machado-Neto JA, et al.

invasion promoted by α6β4 (Shaw 2001). In A375 et al. 2015; Reuveni, et al. 2013), osteosarcoma cells human melanoma cells, the in vitro treatment with (Garofalo, et al. 2015), prostate adenocarcinoma NT157, a IRS1/2 inhibitor, led to growth cells (Ibuki, et al. 2014) and colorectal cancer cells suppression of melanoma cells by degradation of (Sanchez-Lopez, et al. 2015). IRS1 and IRS2 (Reuveni, et al. 2013). Moreover, NT157 strongly inhibited the development of lung References metastases of melanoma cells in mouse models Akker M, Güldiken S, Sipahi T, Palabıyık O, Tosunoğlu A, (Reuveni et al, 2013). Çelik Ö, Tunçbilek N, Sezer A, Süt N. Investigation of insulin Esophageal squamous cell resistance gene polymorphisms in patients with differentiated thyroid cancer. Mol Biol Rep. 2014 carcinoma May;41(5):3541-7 Liu and colleagues (Liu, et al. 2015) identified IRS2 Al-Sarraf N, Reiff JN, Hinrichsen J, Mahmood S, Teh BT, as a target of MicroRNA-146a and suggested that McGovern E, De Meyts P, O'byrne KJ, Gray SG. DOK4/IRS- MicroRNA-146a suppressed esophageal squamous 5 expression is altered in clear cell renal cell carcinoma. Int J Cancer. 2007 Sep 1;121(5):992-8 cell carcinoma growth through inhibition of IRS2. Corroborating these findings, in the MicroRNA- Argetsinger LS, Norstedt G, Billestrup N, White MF, Carter- 146a-expressing EC109 esophageal squamous cell Su C. Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in carcinoma cell line, IRS2 recovery experiments intracellular signaling. J Biol Chem. 1996 Nov increased cell growth. 15;271(46):29415-21 Gastric cancer Boissan M, Beurel E, Wendum D, Rey C, Lécluse Y, Housset C, Lacombe ML, Desbois-Mouthon C. Yamashita et al. (Yamashita, et al. 2006) described Overexpression of insulin receptor substrate-2 in human that IRS2 was methylation-silenced in gastric cancer and murine hepatocellular carcinoma. Am J Pathol. 2005 specimens. Zhao and colleagues (Zhao, et al. 2012), Sep;167(3):869-77 reported that IRS2 G1057D (rs1805097) Burks DJ, Font de Mora J, Schubert M, Withers DJ, Myers polymorphism was associated with increased MG, Towery HH, Altamuro SL, Flint CL, White MF. IRS-2 susceptibility for gastric cancer in a cohort of 197 pathways integrate female reproduction and energy patients with gastric cancer and 156 age- and sex- homeostasis. Nature. 2000 Sep 21;407(6802):377-82 matched controls. Byron SA, Horwitz KB, Richer JK, Lange CA, Zhang X, Yee D. Insulin receptor substrates mediate distinct biological Oral squamous cell carcinoma responses to insulin-like growth factor receptor activation in Gao and colleagues (Gao, et al. 2014) described that breast cancer cells. Br J Cancer. 2006 Nov 6;95(9):1220-8 IRS2 expression was negatively associated with Cantarini MC, de la Monte SM, Pang M, Tong M, D'Errico histological differentiation of oral squamous cell A, Trevisani F, Wands JR. Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked carcinoma. In addition, IRS2 inhibition reduces cell to activation of insulin-like growth factor and notch signaling proliferation, clonogenicity, cell cycle progression mechanisms. Hepatology. 2006 Aug;44(2):446-57 and PI3K/AKT activation in the human oral Carvalheira JB, Ribeiro EB, Folli F, Velloso LA, Saad MJ. squamous cell carcinoma Tca-8113 cell line (Gao, et Interaction between leptin and insulin signaling pathways al. 2014). differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver. Biol Chem. 2003 Jan;384(1):151-9 To be noted Cayan F, Tok E, Aras-Ateş N, Ayaz L, Akbay E, Gen R, Karakaş S, Dilek S. Insulin receptor substrate-2 gene Homozygous absence of the Irs2 gene results in type polymorphism: is it associated with endometrial cancer? II diabetes and causes female infertility in mice Gynecol Endocrinol. 2010 May;26(5):378-82 (Burks, et al. 2000; Withers, et al. 1998). In view of Clark JL, Dresser K, Hsieh CC, Sabel M, Kleer CG, Khan A, the importance of IRS proteins for cancer Shaw LM. Membrane localization of insulin receptor development and progression, a great effort has been substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer. Breast Cancer Res Treat. 2011 made in an attempt to develop or identify compounds Dec;130(3):759-72 capable of inhibiting signaling mediated by IRS proteins. Cui X, Kim HJ, Kuiatse I, Kim H, Brown PH, Lee AV. Epidermal growth factor induces insulin receptor substrate- In this sense, a unique subfamily of IGF1R signaling 2 in breast cancer cells via c-Jun NH(2)-terminal inhibitors (NT compounds) has been developed kinase/activator protein-1 signaling to regulate cell (Reuveni, et al. 2013). NT157, the most migration. Cancer Res. 2006 May 15;66(10):5304-13 characterized NT compound, binds to IGF1R and Cui X, Lazard Z, Zhang P, Hopp TA, Lee AV. Progesterone induces a conformational change, leading to the crosstalks with insulin-like growth factor signaling in breast dissociation of IRS1/2 from the receptor and IRS1/2 cancer cells via induction of insulin receptor substrate-2. degradation by the proteasome. NT157 was found to Oncogene. 2003 Oct 9;22(44):6937-41 lead to long-lasting IGF1R inhibition, apoptosis, and Day E, Poulogiannis G, McCaughan F, Mulholland S, present a potent antitumor effects in melanoma cells Arends MJ, Ibrahim AE, Dear PH. IRS2 is a candidate driver but not in normal melanocytes (Flashner-Abramson,

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oncogene on 13q34 in colorectal cancer. Int J Exp Pathol. therapeutic response of prostate cancer. Mol Cancer Ther. 2013 Jun;94(3):203-11 2014 Dec;13(12):2827-39 Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang Jackson JG, Zhang X, Yoneda T, Yee D. Regulation of X, Divisova J, Britton OL, Mohsin S, Allred DC, Hadsell DL, breast cancer cell motility by insulin receptor substrate-2 Lee AV. Mammary tumorigenesis and metastasis caused by (IRS-2) in metastatic variants of human breast cancer cell overexpression of insulin receptor substrate 1 (IRS-1) or lines. Oncogene. 2001 Nov 1;20(50):7318-25 IRS-2. Mol Cell Biol. 2006 Dec;26(24):9302-14 Johnston JA, Wang LM, Hanson EP, Sun XJ, White MF, Feigelson HS, Teras LR, Diver WR, Tang W, Patel AV, Oakes SA, Pierce JH, O'Shea JJ. Interleukins 2, 4, 7, and Stevens VL, Calle EE, Thun MJ, Bouzyk M. Genetic 15 stimulate tyrosine phosphorylation of insulin receptor variation in candidate obesity genes ADRB2, ADRB3, substrates 1 and 2 in T cells. Potential role of JAK kinases. GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for J Biol Chem. 1995 Dec 1;270(48):28527-30 breast cancer in the Cancer Prevention Study II. Breast Cancer Res. 2008;10(4):R57 Karimi K, Mahmoudi T, Karimi N, Dolatmoradi H, Arkani M, Farahani H, Vahedi M, Parsimehr E, Dabiri R, Nobakht H, Flashner-Abramson E, Klein S, Mullin G, Shoshan E, Song Asadi A, Zali MR. Is there an association between variants R, Shir A, Langut Y, Bar-Eli M, Reuveni H, Levitzki A. in candidate insulin pathway genes IGF-I, IGFBP-3, INSR, Targeting melanoma with NT157 by blocking Stat3 and and IRS2 and risk of colorectal cancer in the Iranian IGF1R signaling. Oncogene. 2016 May 19;35(20):2675-80 population? Asian Pac J Cancer Prev. 2013;14(9):5011-6 Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP. Kim B, Feldman EL. Insulin receptor substrate (IRS)-2, not Angiotensin II inhibits insulin signaling in aortic smooth IRS-1, protects human neuroblastoma cells against muscle cells at multiple levels. A potential role for serine apoptosis. Apoptosis. 2009 May;14(5):665-73 phosphorylation in insulin/angiotensin II crosstalk. J Clin Invest. 1997 Nov 1;100(9):2158-69 Kim B, Leventhal PS, White MF, Feldman EL. Differential regulation of insulin receptor substrate-2 and mitogen- Gao L, Wang X, Wang X, Zhang L, Qiang C, Chang S, Ren activated protein kinase tyrosine phosphorylation by W, Li S, Yang Y, Tong D, Chen C, Li Z, Song T, Zhi K, phosphatidylinositol 3-kinase inhibitors in SH-SY5Y human Huang C. IGF-1R, a target of let-7b, mediates crosstalk neuroblastoma cells. Endocrinology. 1998 between IRS-2/Akt and MAPK pathways to promote Dec;139(12):4881-9 proliferation of oral squamous cell carcinoma. Oncotarget. 2014 May 15;5(9):2562-74 Kim B, van Golen CM, Feldman EL. Insulin-like growth factor-I signaling in human neuroblastoma cells. Oncogene. Garofalo C, Capristo M, Mancarella C, Reunevi H, Picci P, 2004 Jan 8;23(1):130-41 Scotlandi K. Preclinical Effectiveness of Selective Inhibitor of IRS-1/2 NT157 in Osteosarcoma Cell Lines. Front Knobbe CB, Reifenberger G. Genetic alterations and Endocrinol (Lausanne). 2015;6:74 aberrant expression of genes related to the phosphatidylinositol-3'-kinase/protein kinase B (Akt) signal transduction Gibson SL, Ma Z, Shaw LM. Divergent roles for IRS-1 and pathway in glioblastomas. Brain Pathol. 2003 IRS-2 in breast cancer metastasis. Cell Cycle. 2007 Mar Oct;13(4):507-18 15;6(6):631-7 Kornmann M, Maruyama H, Bergmann U, Gunter MJ, Hayes RB, Chatterjee N, Yeager M, Welch R, Tangvoranuntakul P, Beger HG, White MF, Korc M. Schoen RE, Yakochi L, Schatzkin A, Peters U. Insulin Enhanced expression of the insulin receptor substrate-2 resistance-related genes and advanced left-sided colorectal docking protein in human pancreatic cancer. Cancer Res. adenoma. Cancer Epidemiol Biomarkers Prev. 2007 1998 Oct 1;58(19):4250-4 Apr;16(4):703-8 Liu H, Ren G, Zhu L, Liu X, He X. The upregulation of Hoang CD, Zhang X, Scott PD, Guillaume TJ, Maddaus MA, miRNA-146a inhibited biological behaviors of ESCC Yee D, Kratzke RA. Selective activation of insulin receptor through inhibition of IRS2 Tumour Biol 2016 substrate-1 and -2 in pleural mesothelioma cells: Apr;37(4):4641-7 association with distinct malignant phenotypes. Cancer Res. 2004 Oct 15;64(20):7479-85 Ma Y, Kong Q, Hua H, Luo T, Jiang Y. Aflatoxin B1 up- regulates insulin receptor substrate 2 and stimulates Huang F, Chang H, Greer A, Hillerman S, Reeves KA, hepatoma cell migration PLoS One 2012;7(10):e47961 Hurlburt W, Cogswell J, Patel D, Qi Z, Fairchild C, Ryseck RP, Wong TW, Finckenstein FG, Jackson J, Carboni JM. Machado-Neto JA, Favaro P, Lazarini M, da Silva Santos IRS2 copy number gain, KRAS and BRAF mutation status Duarte A, Archangelo LF, Lorand-Metze I, Costa FF, Saad as predictive biomarkers for response to the IGF-1R/IR ST, Traina F. Downregulation of IRS2 in myelodysplastic inhibitor BMS-754807 in colorectal cancer cell lines. Mol syndrome: a possible role in impaired hematopoietic cell Cancer Ther. 2015 Feb;14(2):620-30 differentiation Leuk Res 2012 Jul;36(7):931-5 Huang SP, Bao BY, Hour TC, Huang CY, Yu CC, Liu CC, Mardilovich K, Shaw LM. Hypoxia regulates insulin receptor Lee YC, Huang CN, Pao JB, Huang CH. Genetic variants in substrate-2 expression to promote breast carcinoma cell CASP3, BMP5, and IRS2 genes may influence survival in survival and invasion Cancer Res 2009 Dec 1;69(23):8894- prostate cancer patients receiving androgen-deprivation 901 therapy. PLoS One. 2012;7(7):e41219 Miyagi E, Braga-Basaria M, Hardy E, Vasko V, Burman KD, Ibrahim YH, Byron SA, Cui X, Lee AV, Yee D. Progesterone Jhiang S, Saji M, Ringel MD. Chronic expression of receptor-B regulation of insulin-like growth factor-stimulated RET/PTC 3 enhances basal and insulin-stimulated PI3 cell migration in breast cancer cells via insulin receptor kinase/AKT signaling and increases IRS-2 expression in substrate-2. Mol Cancer Res. 2008 Sep;6(9):1491-8 FRTL-5 thyroid cells Mol Carcinog 2004 Oct;41(2):98-107 Ibuki N, Ghaffari M, Reuveni H, Pandey M, Fazli L, Azuma Morelli C, Garofalo C, Bartucci M, Surmacz E. Estrogen H, Gleave ME, Levitzki A, Cox ME. The tyrphostin NT157 receptor-alpha regulates the degradation of insulin receptor suppresses insulin receptor substrates and augments substrates 1 and 2 in breast cancer cells Oncogene 2003 Jun 26;22(26):4007-16

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Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM. progression from neurofibroma to malignant peripheral Involvement of insulin receptor substrate 2 in mammary nerve sheath tumor Anticancer Res 2012 Feb;32(2):439-43 tumor metastasis Mol Cell Biol 2004 Nov;24(22):9726-35 Shaw LM. Identification of insulin receptor substrate 1 (IRS- Neid M, Datta K, Stephan S, Khanna I, Pal S, Shaw L, White 1) and IRS-2 as signaling intermediates in the alpha6beta4 M, Mukhopadhyay D. Role of insulin receptor substrates integrin-dependent activation of phosphoinositide 3-OH and protein kinase C-zeta in vascular permeability kinase and promotion of invasion Mol Cell Biol 2001 factor/vascular endothelial growth factor expression in Aug;21(15):5082-93 pancreatic cancer cells J Biol Chem 2004 Feb 6;279(6):3941-8 Slattery ML, Sweeney C, Wolff R, Herrick J, Baumgartner K, Giuliano A, Byers T. Genetic variation in IGF1, IGFBP3, Park DH, Jeon HS, Lee SY, Choi YY, Lee HW, Yoon S, Lee IRS1, IRS2 and risk of breast cancer in women living in JC, Yoon YS, Kim DS, Na MJ, Kwon SJ, Kim DS, Kang J, Southwestern United States Breast Cancer Res Treat 2007 Park JY, Son JW. MicroRNA-146a inhibits epithelial Aug;104(2):197-209 mesenchymal transition in non-small cell lung cancer by targeting insulin receptor substrate 2 Int J Oncol 2015 Stöhr O, Hahn J, Moll L, Leeser U, Freude S, Bernard C, Oct;47(4):1545-53 Schilbach K, Markl A, Udelhoven M, Krone W, Schubert M. Insulin receptor substrate-1 and -2 mediate resistance to Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White glucose-induced caspase-3 activation in human MF, Kahn CR. 4PS/insulin receptor substrate (IRS)-2 is the neuroblastoma cells Biochim Biophys Acta 2011 alternative substrate of the insulin receptor in IRS-1- May;1812(5):573-80 deficient mice J Biol Chem 1995 Oct 20;270(42):24670-3 Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG Jr, Platanias LC, Uddin S, Yetter A, Sun XJ, White MF. The Glasheen E, Lane WS, Pierce JH, White MF. Role of IRS-2 type I interferon receptor mediates tyrosine phosphorylation in insulin and cytokine signalling Nature 1995 Sep of insulin receptor substrate 2 J Biol Chem 1996 Jan 14;377(6545):173-7 5;271(1):278-82 Szabolcs M, Keniry M, Simpson L, Reid LJ, Koujak S, Schiff Porter HA, Perry A, Kingsley C, Tran NL, Keegan AD. IRS1 SC, Davidian G, Licata S, Gruvberger-Saal S, Murty VV, is highly expressed in localized breast tumors and regulates Nandula S, Efstratiadis A, Kushner JA, White MF, Parsons the sensitivity of breast cancer cells to chemotherapy, while R. Irs2 inactivation suppresses tumor progression in Pten+/- IRS2 is highly expressed in invasive breast tumors Cancer mice Am J Pathol 2009 Jan;174(1):276-86 Lett 2013 Sep 28;338(2):239-48 Uddin S, Yenush L, Sun XJ, Sweet ME, White MF, Platanias Rashad NM, El-Shal AS, Abd Elbary EH, Abo Warda MH, LC. Interferon-alpha engages the insulin receptor Hegazy O. Impact of insulin-like growth factor 2, insulin-like substrate-1 to associate with the phosphatidylinositol 3'- growth factor receptor 2, insulin receptor substrate 2 genes kinase J Biol Chem 1995 Jul 7;270(27):15938-41 polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma Cytokine 2014 Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR. Jul;68(1):50-8 Cross-talk between the insulin and angiotensin signaling systems Proc Natl Acad Sci U S A 1996 Oct Reuveni H, Flashner-Abramson E, Steiner L, Makedonski 29;93(22):12490-5 K, Song R, Shir A, Herlyn M, Bar-Eli M, Levitzki A. Therapeutic destruction of insulin receptor substrates for Verdier F, Chrétien S, Billat C, Gisselbrecht S, Lacombe C, cancer treatment Cancer Res 2013 Jul 15;73(14):4383-94 Mayeux P. Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2 An alternate Saad MJ, Carvalho CR, Thirone AC, Velloso LA. Insulin pathway for erythropoietin-induced phosphatidylinositol 3- induces tyrosine phosphorylation of JAK2 in insulin- kinase activation J Biol Chem sensitive tissues of the intact rat J Biol Chem 1996 Sep 6;271(36):22100-4 White MF, Kahn CR. The insulin signaling system J Biol Chem 1994 Jan 7;269(1):1-4 Saad MJ, Velloso LA, Carvalho CR. Angiotensin II induces tyrosine phosphorylation of insulin receptor substrate 1 and Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, its association with phosphatidylinositol 3-kinase in rat heart Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner- Biochem J 1995 Sep 15;310 ( Pt 3):741-4 Weir S, White MF. Disruption of IRS-2 causes type 2 diabetes in mice Nature 1998 Feb 26;391(6670):900-4 Sanchez-Lopez E, Flashner-Abramson E, Shalapour S, Zhong Z, Taniguchi K, Levitzki A, Karin M. Targeting Wu S, Zhou B, Xu L, Sun H. Interaction between nuclear colorectal cancer via its microenvironment by inhibiting IGF- insulin receptor substrate-2 and NF-κB in IGF-1 induces 1 receptor-insulin receptor substrate and STAT3 signaling response in breast cancer cells Oncol Rep 2010 Oncogene 2016 May 19;35(20):2634-44 Dec;24(6):1541-50 Zhao XM, Chen J, Yang L, Luo X, Xu LL, Liu DX, Zhai SL, Xu J, Liao X, Lu N, Liu W, Wong CW. Chromatin-modifying Li P, Wang XR. Association between IRS-2 G1057D drugs induce miRNA-153 expression to suppress Irs-2 in polymorphism and risk of gastric cancer World J glioblastoma cell lines Int J Cancer 2011 Nov Gastrointest Oncol 2012 Jan 15;4(1):9-15 15;129(10):2527-31 Savage SL, Eide CA, Concannon KF, Bottomly D, Wilmot Yamashita S, Tsujino Y, Moriguchi K, Tatematsu M, B, McWeeney SK, Maxson JE, Tyner JW, Tognon CE and Ushijima T. Chemical genomic screening for methylation- Druker BJ.. Activating Mutations of Insulin Receptor silenced genes in gastric cancer cell lines using 5-aza-2'- Substrate 2 (IRS2) in Patients with Tyrosine Kinase deoxycytidine treatment and oligonucleotide microarray Inhibitor-Refractory Chronic Myeloid Leukemia.E Blood Cancer Sci 2006 Jan;97(1):64-71 (ASH Annual Meeting Abstracts) 2015 126 (23): Abstract #2461. Yenush L, White MF. The IRS-signalling system during insulin and cytokine action Bioessays 1997 Jun;19(6):491- Shaw CM, Grobmyer SR, Ucar DA, Cance WG, Reith JD, 500 Hochwald SN. Elevated expression of IRS2 in the

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 42

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Yukseloglu EH, Celik SK, Kucuk MU, Yalin E, Ozkal SS, Zhao XM, Chen J, Yang L, Luo X, Xu LL, Liu DX, Zhai SL, Ates C, Berkoz M, Yalin S, Ates NA. IRS-2 G1057D Li P, Wang XR. Association between IRS-2 G1057D polymorphism in Turkish patients with colorectal cancer Prz polymorphism and risk of gastric cancer World J Gastroenterol 2014;9(2):88-92 Gastrointest Oncol 2012 Jan 15;4(1):9-15 Zekri AR, Hassan ZK, Bahnassy AA, Khaled HM, El-Rouby de Melo Campos P, Machado-Neto JA, Eide CA, Savage MN, Haggag RM, Abu-Taleb FM. Differentially expressed SL, Scopim-Ribeiro R, da Silva Souza Duarte A, Favaro P, genes in metastatic advanced Egyptian bladder cancer Lorand-Metze I, Costa FF, Tognon CE, Druker BJ, Olalla Asian Pac J Cancer Prev 2015;16(8):3543-9 Saad ST, Traina F. IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive Zhang Q, Berggren PO, Hansson A, Tally M. Insulin-like myeloproliferative neoplasms Oncotarget 2016 Feb growth factor-I-induced DNA synthesis in insulin-secreting 9;7(6):6948-59 cell line RINm5F is associated with phosphorylation of the insulin-like growth factor-I receptor and the insulin receptor This article should be referenced as such: Machado-Neto JA, de Melo Campos P, Traina F. IRS2 substrate-2 J Endocrinol 1998 Mar;156(3):573-81 (insulin receptor substrate 2). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2):35-43. Zhang X, Kamaraju S, Hakuno F, Kabuta T, Takahashi S, Sachdev D, Yee D. Motility response to insulin-like growth factor-I (IGF-I) in MCF-7 cells is associated with IRS-2 activation and integrin expression Breast Cancer Res Treat 2004 Jan;83(2):161-70

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 43 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

HNF4A (Hepatocyte Nuclear Factor 4 alpha) Sinem Tunçer, Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Published in Atlas Database: June 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/HNF4AID44014ch20q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68157/06-2016-HNF4AID44014ch20q13.pdf DOI: 10.4267/2042/68157 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 differentiation, embryogenesis and organogenesis. Keywords: HNF4A Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 (Nuclear Receptor Subfamily 2, Identity group A, member 1) is a member of the nuclear receptor (NR) superfamily of ligand-dependent HGNC (Hugo): HNF4A transcription factors. The encoded protein controls Location the expression of several genes, especially those that The human HNF4A gene is located on 20q12-q13.1 play distinct roles in development,

Figure 1 HNF4A transcripts. HNF4A contains two distinct promoters (P1 and P2) that drive expression of 9 known isoforms (α1 to α9) of the gene. Transcription through the P1 promoter allows transcription starting from exon 1 (B) coding for the N- terminal domain of HNF4A, designated as AF-1. Transcription through the P2 promoter allows the inclusion of exon 1 (A) but the exclusion of the exon 1 (B). Although alternative splicing of exon 1 (B) modifies only A/B domain of the P1 isoforms, F domains of both isoforms are modified by alternative splicing of the last exons. DBD: DNA binding domain; LBD: Ligand binding domain; AF-1: Activating function-1; AF-2: Activating function-2 (Modified from Babeu and Boudreau, 2014).

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 44 HNF4A (Hepatocyte Nuclear Factor 4 alpha) Tunçer S, Banerjee S

Figure 2 HNF4A domains. AF-1: activation function; DBD: DNA binding function; LBD: ligand binding function; F domain: repressor function that inhibits access of coactivators to NCOA5 (AF-2) which function in homodimerization and activation. H: hinge region.

(CBP/P300), PPARGC1A (PGC1)) (MartÍnez- DNA/RNA Jiménez et al., 2006). Description Expression The human HNF4A gene spans ~77 kb. Multiple HNF4A isoforms exist in humans and are suggested to have different physiological roles in Transcription development and transcriptional regulation of target The HNF4A gene is composed of thirteen exons and genes (Figure 1). HNF4A1 and 2 isoforms from the contains two promoters, P1 and P2, which can drive P1 promoter are expressed in the liver (hepatocytes), the expression of many splice variants (HNF4A1- kidneys, small intestine and colon. HNF4A3 and 4 HNF4A9) that differ in the variable A/B and F are expressed in human liver. P2 promoter-driven domains (Harries et al., 2008). The variants derived HNF4A7 and 8 are expressed in the fetal liver and from the P1 and P2 promoters are referred to as adult pancreas (β-cells) and to a lesser extent in the HNF4A1-HNF4A6 and HNF4A7-HNF4A9, adult liver (bile ducts), small intestine, colon and respectively (Erdmann et al., 2007). stomach. HNF4A isoforms from both the P1 and P2 The different promoters are used in different tissues promoter were also reported to be expressed in the and at different times during development, and the epididymis (Tanaka et al., 2006). However, not encoded protein controls the expression of several much is known about the developmental and genes. Multiple isoforms are proposed to exist in physiological relevance of the HNF4A isoforms mammals and are thought to have different (Boyd et al., 2009). physiological roles in development and In addition to several different isoforms produced differentiation (Walesky and Apte, 2015). from the HNF4A gene by different promoter usage and alternative splicing, the 3'UTR of the gene was Protein also reported to control HNF4A expression (Wirsing et al., 2011). Description Localisation Domain structure and DNA binding Localized primarily in the nucleus. HNF4A consists of six structural domains named A- F that are responsible for specific functions: an N- Function terminal activation domain (AF-1, also referred to as HNF4A can exist in an unliganded form, or may bind A/B domain); a zinc finger domain that serves as the to linoleic acid (LA), an essential fatty acid (Yuan et DNA-binding domain (DBD; C domain) which is al., 2009). Although it is not yet clear whether ligand highly conserved among NRs; a putative ligand binding affects the function of HNF4A, the HNF4A binding domain (LBD; E domain); and a C-terminal transcriptional activity is regulated at several domain which functions in homodimerization and different levels. Most prominent among the post- activation (AF-2), and a repressor region (F domain) translational modifications of HNF4A is that inhibits access of coactivators to AF-2, and phosphorylation which occurs mainly at serine and possibly to other regions (Walesky and Apte, 2015). to a lesser extent at threonine residues (Jiang et al., The DBD consists of two zinc fingers, and 12 alpha 1997). Between the kinases, PRKACA (protein helices that create a hydrophobic pocket for ligand kinase A, PKA) dependent phosphorylation of binding (Duda et al., 2004) (Figure 2). HNF4A was reported to inhibit recruitment to target HNF4A binds DNA regulatory elements as a genes (You et al., 2002). On the other hand, homodimer. E domain (Ligand Binding Domain- activation of MAP kinase pathway was shown to LBD) appears to be critical for homodimerization down-regulate HNF4A transcription (Reddy et al., and to play a role in preventing heterodimerization 1999). AMP-activated protein kinase was also with other NRs such as RXR or RAR (Bogan et al., implicated in the regulation of HNF4A activity by 2000). HNF4A binds DNA response elements inhibiting dimer formation and decreasing protein consisting of direct repeats. It can also bind several stability (Hong et al., 2003). p38 kinase-mediated different co-activators (such as GRIP1, NCOA1, Ser158 phosphorylation was also shown to increase NCOA2, NCOA3, (SRC1, 2 and 3), CREBBP DNA binding and transactivation potential of

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HNF4A (Hepatocyte Nuclear Factor 4 alpha) Tunçer S, Banerjee S

HNF4A (Guo et al., 2006), and Ser78 HNF4A was also found to be related to epithelial cell phosphorylation of HNF4A by PRKCB (protein adhesion and junction formation in the fetal liver kinase C, PKC) was shown to down-regulate (Battle et al., 2006). Re-expression of HNF4A was HNF4A protein level via the proteasome pathway shown to induce cells to reform junctions and (Sun et al., 2007). express hepatocyte marker genes in a Acetylation was also implicated in the regulation of dedifferentiated hepatoma cell line (Späth and HNF4A function (Soutoglou et al., 2000; Yokoyama Weiss, 1997; Späth and Weiss, 1998). More et al., 2011). Soutoglou et al. showed that CREB- recently, HNF4A was implicated in the binding protein (CBP) acetylates HNF4A on lysine differentiation of hepatic stellate cells into residues within the nuclear localization sequence, hepatocyte-like cells (Liu et al., 2015). Furthermore, and increase nuclear retention and target gene in non-hepatic cells, ectopic over expression of activation by HNF4A (Soutoglou et al., 2000). HNF4A in fibroblasts induced mesenchymal to Methylation and SUMOylation are the other post- epithelial transition (EMT), indicating that HNF4A translational mechanisms that regulate HNF4A is a dominant regulator of the morphogenetic activity. Methylation of the DNA-binding domain of parameters that form the epithelial phenotype HNF4A by PRMT1 (Protein Arginine (Parviz et al., 2003.). Methyltransferase 1), whose methylation activity on More recently, Yang et al. showed that during EMT, HIST4H4 (histone H4 )strongly correlates with the there is a negative feedback loop between Wnt-β- induction of HNF4A target genes in differentiating catenin signaling and HNF4A, both in vivo and in enterocytes, increased transcriptional activity of vitro. Restoring HNF4A expression was suggested HNF4A (Barrero and Malik, 2006). SUMOylation is as a method to inhibit invasion in hepatocellular the other mechanism that regulates HNF4A protein carcinoma by preventing EMT (Yang et al., 2013). stability and potentially DNA binding activity (Zhou Intestine et al., 2012). HNF4A plays essential roles in the intestine, As a transcription factor, HNF4A was first identified particularly in epithelial cell function, differentiation to be bound to DNA sites required for the and normal colon physiology (Chellappa et al., transcription of two liver-specific genes: TTR 2012). (transthyretin) and APO3 (apolipoprotein CIII) To directly address the role of HNF4A in (Sladek et al., 1990). An increasing number of development of the colon, an epithelial-specific studies implicate a vital role of HNF4A in the knockout model of HNF4A was created in mice by development of the liver, intestine and pancreas, using the Cre-loxP system. Examination of the differentiation and homeostasis (Figure 3). embryos revealed that HNF4A ablation disrupts Liver development of normal crypt topology in fetal HNF4A has been shown to be required for colons, and reduced goblet cell maturation (Garrison hepatocyte differentiation and development of the et al., 2006). In adult small intestine, HNF4A was liver. The expression of HNF4A mRNA in post- shown to play a critical role in the homeostasis of implantation mouse embryos was found in the intestinal epithelium, in the epithelial cell primary endoderm starting at day 4.5. From day 8.5, architecture, and in the barrier function of the HNF4A mRNA was detected in embryonic tissues in intestine. Loss of intestinal HNF4A affected the the liver diverticulum and the hindgut. At later times, Wnt/β-catenin signaling pathway, and destabilized HNF4A transcripts were found in the mesonephric adherens and tight junctions (Cattin et al., 2009). tubules, pancreas, stomach, intestine, and in the Recently, Vuong et al. suggested that HNF4A metanephric tubules of the developing kidney isoforms play distinct roles in colon cancer, which (Duncan et al., 1994). Additionally, conditional could be caused by differential interactions with the genetic removal of HNF4A in the liver resulted in Wnt/β-catenin/TCF4 and AP-1 pathways (Vuong et disorganization of morphological and functional al., 2015). differentiation in the hepatic epithelium (Parviz et Importance of HNF4A in the formation of tight al., 2003). In hepatocyte-specific knock-out model, epithelial barrier to exert a selective barrier function lack of HNF4A expression in the liver caused in relation to apical-to-basal transport was also impaired lipid metabolism and gluconeogenesis shown in a coculture system (Lussier et al., 2008). (Hayhurst et al., 2001), indicating that HNF4A Besides nutrient metabolism (Black, 2007) and controls genes involved in hepatic lipid and glucose protection against pathogens (Laukoetter et al., metabolism, hereby influencing the hepatocyte 2006), another function of the epithelial barrier is the metabolome (Parviz et al., 2003). On the other hand, control of appropriate ion selectivity. Loss of this homozygous loss of HNF4A gene resulted in function can lead to deregulation of colonic embryonic lethality (Chen et al., 1994.). inflammatory homeostasis and inflammatory bowel disease (IBD) (Darsigny et al., 2009).

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Differentiation program in the colon Figure 3 HNF4A can regulate different cell functions. HNF4A is an important regulator with a strong impact on endodermal development, organ differentiation and metabolism (Boyd et al., 2009).

HNF4A appears to play a protective role against HNF4A activity is essential for β-cell function IBD, an important risk factor for colorectal cancer. through the regulation of several genes, including In patients with IBD, HNF4A expression was those involved in metabolism-secretion coupling, significantly decreased. Accordingly, intestine such as glucose transporter-2, L-pyruvate kinase, specific HNF4A-null mice exhibited increased aldolase B, 2-oxoglutarate dehydrogenase E1 susceptibility to dextran sulfate sodium (DSS) subunit, mitochondrial uncoupling protein-2 (Wang induced IBD with increased intestinal permeability, et al., 2000) and the potassium channel subunit suggesting that HNF4A was required to protect the Kir6.2 (Gupta et al., 2005), as well as the INS epithelium during experimental colitis (Ahn et al., (insulin gene) (Wang et al, 2000; Bartoov-Shifman 2008). et al., 2002). In pancreatic β-cells, HNF4A maintains HNF4A was also addressed as a crucial transcription glucose homeostasis (Marcil et al., 2015; Wang et factor in the differentiation of intestinal cells. al., 2000). Gene expression analysis in type 2 Intestine specific knockout of HNF4A in the adult diabetes (T2D) patients compared to normal mouse enhanced proliferation in crypts, and glucose-tolerant controls revealed that HNF4A increased number of mucus secreting cells (Cattin et mRNA level decreased in pancreatic β-cells of T2D al., 2009). patients (Gunton et al., 2005). Moreover, HNF4A HNF4A was also shown to be involved in the mutations were implicated in Mature-Onset Diabetes regulation of genes involved in the enterocyte of the Young 1 (MODYI), a dominantly inherited differentiation and in lipid metabolism (Béaslas et atypical subgroup of T2D characterized by al., 2008; Stegmann et al. 2006; Cattin et al., 2009). decreased glucose stimulated insulin secretion in To address the role of HNF4A in differentiation pancreatic β-cells (Yamagata et al., 1996). More dependent transcription in human colonic epithelial recently, it was suggested lack of HNF4A function cells, Boyd et al. performed a genome-wide disrupts Ca2+ signaling and insulin release in β-cells identification of promoters that are occupied by of patients with MODYI through altered HNF4A in vivo. endoplasmic reticulum (ER) Ca2+ homeostasis The analysis revealed that HNF4A was mostly (Moore et al., 2016). associated with the promoter regions involved in transport and metabolism. Homology HNF4A was found to regulate differentiation HNF4A is highly conserved across species, with dependent transcription by regulating the expression 100% amino acid conservation in the DNA binding of HNF1A and CDX2, transcription factors domain of all mammalian HNF4A. HNF4A has been necessary for the expression of many intestinal genes found in every animal organism examined thus far, important in the development and differentiation including sponge and coral, and has been postulated program in the colon (Boyd et al., 2009). to be the ancestor of the entire NR family (Bolotin et al., 2011) (Table 1 and Figure 4). Pancreas

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HNF4A (Hepatocyte Nuclear Factor 4 alpha) Tunçer S, Banerjee S

Table 1 Pairwise alignment of HNF4A gene and protein sequences (in distance from human). HNF4A is highly conserved evolutionarily.

Figure 4 HNF4A proteins and their conserved domain architectures. HNF4A is a member of the nuclear receptor (NR) family of transcription factors that use conserved DNA binding domains (DBDs) and ligand binding domains (LBDs).

cholesterol (HDL-C) (Teslovich et al., 2010) and Mutations metabolic dyslipidemia (Suviolahti et al., 2006). HNF4A is at the center of a complex transcriptional Finally, since it regulates several Phase I/II and other regulatory network and is implicated to several genes in the liver, HNF4A is suggested to play a role human diseases including diabetes (Mohlke and in drug metabolism (Hwang-Verslues and Sladek, Boehnke, 2005), MODY1 (Ryffel, 2001), 2010). In addition, polymorphisms (Hwang- hemophilia (Reijnen et al., 1992) and hepatitis B Verslues and Sladek, 2010; Ruchat et al., 2009; viral infections (He et al., 2012). The HNF4A locus Marcil et al., 2015) and mutations (Ryffel, 2001) in has been associated with high-density lipoprotein the human HNF4A gene are associated with altered expression and transcriptional activity.

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Germinal develop MODY1 (Glaser, 2013). The transmission is autosomal dominant with variable penetrance Diabetes mellitus, noninsulin-dependent (Pearson et al., 2007; Kapoor et al., 2008). (NIDDM): In early disease onset, three mutations affecting HNF4A function were identified (D126Y; D126H; Implicated in R154Q) (Aguilar-Salinas et al., 2001). In late onset, Gastric adenocarcinoma missense mutations were identified in the LBD (R323H) (Price et al., 2000) and the F domain HNF4A expression was seen in primary gastric (V393I); the latter resulted in a reduced adenocarcinomas and in metastases of gastric transactivational activity (Hani et. al., 1998). V255M carcinoma to the breast, but was absent in primary mutation has also been shown to reduce breast carcinomas, and in metastases of breast transactivation, albeit modestly (Mohlke and carcinomas to the stomach (van der Post t al., 2014). Boehnke, 2005). Thirteen single nucleotide polymorphisms (SNPs) in References the P2 promoter, three of which were identified in Arbini AA, Pollak ES, Bayleran JK, High KA, Bauer KA. Pima Indians, have also been associated with T2D Severe factor VII deficiency due to a mutation disrupting a (Muller et al. 2005). A 7 bp deletion in the Sp1 site hepatocyte nuclear factor 4 binding site in the factor VII of the P1 promoter was identified in type II diabetic promoter. Blood. 1997 Jan 1;89(1):176-82 nephropathic Caucasian patients (Price et al., 2000). Béaslas O, Torreilles F, Casellas P, Simon D, Fabre G, Factor VII deficiency: Lacasa M, Delers F, Chambaz J, Rousset M, Carrière V. Transcriptome response of enterocytes to dietary lipids: Homozygous mutation for a T to G transversion at impact on cell architecture, signaling, and metabolism nucleotide -61 position in the factor VII promoter genes. Am J Physiol Gastrointest Liver Physiol. 2008 was shown to disrupt HNF4A binding and result in a Nov;295(5):G942-52 significant reduction in factor VII promoter activity Barrero MJ, Malik S. Two functional modes of a nuclear (Arbini et al., 1997). receptor-recruited arginine methyltransferase in Maturity-onset diabetes of the young, type 1 transcriptional activation. Mol Cell. 2006 Oct 20;24(2):233- (MODY1): 43 Mutations in the HNF4A coding region and Barrio R, Bellanné-Chantelot C, Moreno JC, Morel V, Calle promoter were shown to be directly implicated in H, Alonso M, Mustieles C. Nine novel mutations in maturity- onset diabetes of the young (MODY) candidate genes in 22 MODY1 in several different human populations Spanish families. J Clin Endocrinol Metab. 2002 (Ryffel, 2001). Jun;87(6):2532-9 Two deletion mutations (F75fsdelT and Bolotin E, Chellappa K, Hwang-Verslues W, Schnabl JM, K99fsdelAA) generate truncated proteins lacking Yang C, Sladek FM. Nuclear receptor HNF4α binding part of the zinc finger domain essential for DNA sequences are widespread in Alu repeats. BMC Genomics. binding. An in-frame insertion mutation, V328ins, 2011 Nov 15;12:560 located in the LBD, was suggested to alter the highly Boyd M, Bressendorff S, Møller J, Olsen J, Troelsen JT. conserved structural organization of the protein. Mapping of HNF4alpha target genes in intestinal epithelial R154X and Q268X nonsense mutants retain the cells. BMC Gastroenterol. 2009 Sep 17;9:68 DNA binding domain but lack a substantial portion Darsigny M, Babeu JP, Dupuis AA, Furth EE, Seidman EG, of the potential ligand binding part (Ryffel, 2001). Lévy E, Verdu EF, Gendron FP, Boudreau F. Loss of R127W and E276Q missense mutations were hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling reported to result in a significant loss of HNF4A inflammatory bowel disease in mice. PLoS One. 2009 Oct activity (Lausen et al., 2000). The HNF4A mutations 29;4(10):e7609 G115S (Oxombre et al., 2004.); R127W (Furuta et Duda K, Chi YI, Shoelson SE. Structural basis for HNF- al., 1997); R244Q (Hara et al., 2002.); R324H (Price 4alpha activation by ligand and coactivator binding. J Biol et al., 2000.); IVS5-2delA (Barrio et al., 2002) have Chem. 2004 May 28;279(22):23311-6 also been associated with MODY1. Of note, -146T- Erdmann S, Senkel S, Arndt T, Lucas B, Lausen J, Klein- >C in the P2 promoter region was reported to be Hitpass L, Ryffel GU, Thomas H. Tissue-specific associated with MODY1 by affecting PDX1 (IPF-1) transcription factor HNF4alpha inhibits cell proliferation and binding to DNA (Thomas et al., 2001). induces apoptosis in the pancreatic INS-1 beta-cell line. Biol Chem. 2007 Jan;388(1):91-106 Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A): Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Familial hyperinsulinism due to HNF4A deficiency Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, Omori Y, Iwamoto Y, Bell GI. Organization and partial is a form of diazoxide-sensitive diffuse sequence of the hepatocyte nuclear factor-4 alpha/MODY1 hyperinsulinism (DHI), characterized by gene and identification of a missense mutation, R127W, in macrosomia, transient or persistent a Japanese family with MODY. Diabetes. 1997 hyperinsulinemic hypoglycemia (HH), Oct;46(10):1652-7 responsiveness to the diazoxide and a propensity to Glaser B. Familial Hyperinsulinism 2003 Aug 19 [Updated 2013 Jan 24]. In: Pagon RA, Adam MP, Ardinger HH, et al.,

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 49

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editors. GeneReviews [Internet]. Seattle (WA): University of nuclear factor 4alpha are modestly associated with type 2 Washington, Seattle; 1993-2016. Available from: diabetes in Pima Indians Diabetes 2005 Oct;54(10):3035-9 http://www.ncbi.nlm.nih.gov/books/NBK1375/ Oxombre B, Kouach M, Moerman E, Formstecher P, Laine Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, B. The G115S mutation associated with maturity-onset Tseng YH, Roberson RS, Ricordi C, O'Connell PJ, diabetes of the young impairs hepatocyte nuclear factor Gonzalez FJ, Kahn CR. Loss of ARNT/HIF1beta mediates 4alpha activities and introduces a PKA phosphorylation site altered gene expression and pancreatic-islet dysfunction in in its DNA-binding domain Biochem J 2004 Nov 1;383(Pt human type 2 diabetes Cell 2005 Aug 12;122(3):337-49 Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield Guo H, Gao C, Mi Z, Wai PY, Kuo PC. Phosphorylation of JP, Ellard S, Ferrer J, Hattersley AT. Macrosomia and Ser158 regulates inflammatory redox-dependent hyperinsulinaemic hypoglycaemia in patients with hepatocyte nuclear factor-4alpha transcriptional activity heterozygous mutations in the HNF4A gene PLoS Med Biochem J 2006 Mar 1;394(Pt 2):379-87 2007 Apr;4(4):e118 Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer Reddy S, Yang W, Taylor DG, Shen Xq, Oxender D, Kust JT, Matschinsky FM, Duncan SA, Kaestner KH. The G, Leff T. Mitogen-activated protein kinase regulates MODY1 gene HNF-4alpha regulates selected genes transcription of the ApoCIII gene Involvement of the orphan involved in insulin secretion J Clin Invest 2005 nuclear receptor HNF4 J Biol Chem Apr;115(4):1006-15 Ruchat SM, Weisnagel JS, Rankinen T, Bouchard C, Vohl Hara K, Noda M, Waki H, Tobe K, Yamauchi T, Kadowaki MC, Pérusse L. Interaction between HNF4A polymorphisms H, Satou H, Tsukamoto K, Nagamatsu S, Yamagata K, and physical activity in relation to type 2 diabetes-related Matsuzawa Y, Akanuma Y, Kimura S, Kadowaki T. Maturity- traits: results from the Quebec Family Study Diabetes Res onset diabetes of the young resulting from a novel mutation Clin Pract 2009 Jun;84(3):211-8 in the HNF-4alpha gene Intern Med 2002 Oct;41(10):848- 52 Ryffel GU. Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor Harries LW, Locke JM, Shields B, Hanley NA, Hanley KP, (HNF)1 and HNF4 families: functional and pathological Steele A, Njølstad PR, Ellard S, Hattersley AT. The diabetic consequences J Mol Endocrinol 2001 Aug;27(1):11-29 phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during Sladek FM, Zhong WM, Lai E, Darnell JE Jr. Liver-enriched fetal development Diabetes 2008 Jun;57(6):1745-52 transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily Genes Dev 1990 He F, Chen EQ, Liu L, Zhou TY, Liu C, Cheng X, Liu FJ, Dec;4(12B):2353-65 Tang H. Inhibition of hepatitis B Virus replication by hepatocyte nuclear factor 4-alpha specific short hairpin Stegmann A, Hansen M, Wang Y, Larsen JB, Lund LR, Ritié RNA Liver Int 2012 May;32(5):742-51 L, Nicholson JK, Quistorff B, Simon-Assmann P, Troelsen JT, Olsen J. Metabolome, transcriptome, and bioinformatic Jiang G, Nepomuceno L, Yang Q, Sladek FM. cis-element analyses point to HNF-4 as a central regulator Serine/threonine phosphorylation of orphan receptor of gene expression during enterocyte differentiation Physiol hepatocyte nuclear factor 4 Arch Biochem Biophys 1997 Genomics 2006 Oct 11;27(2):141-55 Apr 1;340(1):1-9 Sun K, Montana V, Chellappa K, Brelivet Y, Moras D, Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Maeda Y, Parpura V, Paschal BM, Sladek FM. Hattersley AT, Ellard S, Hussain K. Persistent Phosphorylation of a conserved serine in the hyperinsulinemic hypoglycemia and maturity-onset deoxyribonucleic acid binding domain of nuclear receptors diabetes of the young due to heterozygous HNF4A alters intracellular localization Mol Endocrinol 2007 mutations Diabetes 2008 Jun;57(6):1659-63 Jun;21(6):1297-311 Laukoetter MG, Bruewer M, Nusrat A. Regulation of the Suviolahti E, Lilja HE, Pajukanta P. Unraveling the complex intestinal epithelial barrier by the apical junctional complex genetics of familial combined hyperlipidemia Ann Med Curr Opin Gastroenterol 2006 Mar;22(2):85-9 2006;38(5):337-51 Lausen J, Thomas H, Lemm I, Bulman M, Borgschulze M, Walesky C, Apte U. Role of hepatocyte nuclear factor 4α Lingott A, Hattersley AT, Ryffel GU. Naturally occurring (HNF4α) in cell proliferation and cancer Gene Expr mutations in the human HNF4alpha gene impair the function 2015;16(3):101-8 of the transcription factor to a varying degree Nucleic Acids Res 2000 Jan 15;28(2):430-7 Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI. Mutations in Martínez-Jimé CP, Gómez-Lechó MJ, Castell JV, Jover R. the hepatocyte nuclear factor-4alpha gene in maturity-onset Underexpressed coactivators PGC1alpha and SRC1 impair diabetes of the young (MODY1) Nature 1996 Dec hepatocyte nuclear factor 4 alpha function and promote 5;384(6608):458-60 dedifferentiation in human hepatoma cells J Biol Chem 2006 Oct 6;281(40):29840-9 Yokoyama A, Katsura S, Ito R, Hashiba W, Sekine H, Mohlke KL, Boehnke M. The role of HNF4A variants in the Fujiki R, Kato S. Multiple post-translational modifications in risk of type 2 diabetes Curr Diab Rep 2005 Apr;5(2):149-56 hepatocyte nuclear factor 4α Biochem Biophys Res Commun 2011 Jul 15;410(4):749-53 Moore BD, Jin RU, Lo H, Jung M, Wang H, Battle MA, Wollheim CB, Urano F, Mills JC. Transcriptional Regulation You M, Fischer M, Cho WK, Crabb D. Transcriptional of X-Box-binding Protein One (XBP1) by Hepatocyte control of the human aldehyde dehydrogenase 2 promoter Nuclear Factor 4α (HNF4) Is Vital to Beta-cell Function J by hepatocyte nuclear factor 4: inhibition by cyclic AMP and Biol Chem 2016 Mar 18;291(12):6146-57 COUP transcription factors Arch Biochem Biophys 2002 Feb 1;398(1):79-86 Muller YL, Infante AM, Hanson RL, Love-Gregory L, Knowler W, Bogardus C, Baier LJ. Variants in hepatocyte Zhou W, Hannoun Z, Jaffray E, Medine CN, Black JR,

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Greenhough S, Zhu L, Ross JA, Forbes S, Wilmut I, Iredale This article should be referenced as such: JP, Hay RT, Hay DC. SUMOylation of HNF4α regulates protein stability and hepatocyte function J Cell Sci 2012 Tunçer S, Banerjee S. HNF4A (Hepatocyte Nuclear Aug 1;125(Pt 15):3630-5 Factor 4 alpha). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2):44-51.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 51 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Leukaemia Section Short Communication t(8;21)(q22;q22) RUNX1/RUNX1T1 Wilma Kroes, Marian Stevens-Kroef Department of Clinical Genetics, Leiden University Medical Center, Leiden; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. [email protected]; [email protected] Published in Atlas Database: May 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0821ID1019.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68158/05-2016-t0821ID1019.pdf DOI: 10.4267/2042/68158

This article is an update of : Huret JL. t(8;21)(q22;q22). Atlas Genet Cytogenet Oncol Haematol 1997;1(1)

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 Identity Review on t(8;21)(q22;q22) RUNX1/RUNX1T1, See figure below. with data on clinics, and the genes involved.

t(8;21)(q22;q22) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (top) and Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap; R- banding (middle) - above: Jean Loup Huret; 2nd row: - Courtesy Christiane Charrin; 3rd and 4th row: - Courtesy Roland Berger. Right: FISH - Courtesy Hossein Mossafa.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 52 t(8;21)(q22;q22) RUNX1/RUNX1T1 Kroes W, Stevens-Kroef M

Translocation t(8;21) is found in 5-12% of AML. Among the non-random chromosomal aberrations observed in AML, t(8;21)(q22;q22) is one of the best known and usually correlates with AML M2, with well defined and specific morphological features. The common morphological features include the presence of large blast cells with abundant basophilic cytoplasm, often containing numerous azurophilic granulations; few blasts in some cases show very large granules (pseudo-Chediak-Higashi granules), suggesting abnormal fusion. Auer rods are frequently found. In addition to the large blast cells, there are also some smaller blasts, predominantly found in the peripheral blood. Promyelocytes, myelocytes and mature granulocytes with variable dysplasia are seen in the bone marrow. These cells may show abnormal nuclear segmentation and/or cytoplasmic staining defects including homogeneous pink colored cytoplasm - Text and iconography Courtesy Georges Flandrin 2001.

AML M2 (FAB classification). The most frequent Clinics and pathology anomaly in chilhood AML; seen in children and adults: mean age 30yrs, rare in elderly patients. Disease Clinics Acute myeloid leukemia (AML) with t(8;21)(q22;q22) is part of the Group of AML with Myeloid sarcomas may be present at presentation. recurrent genetic abnormalities. Prognosis Phenotype/cell stem origin Complete remission (CR) in most cases (90%) with relatively long disease-free survival when treated M2 mostly, rarely: M1 or M4 with high dose chemotherapy. Epidemiology Cytology Annual incidence: 1/106; 5% of AML, 10% of prior See figure and legend.

t(8;21)(q22;q22): cohybridization experiments using dJ155L8 (RUNX1T1) and dJ1107L6 (RUNX1 ); note the splitting of RUNX1 and colocalization on der(8) with RUNX1T1 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

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t(8;21)(q22;q22) RUNX1/RUNX1T1 Kroes W, Stevens-Kroef M

RUNX1 and RUNX1T1 breakpoints in the t(8;21) / 5' RUNX1 - 3' RUNX1T1 fusion gene, and FISH - Courtesy Hossein Mossafa.

Cytogenetics Genes involved and Cytogenetics molecular proteins Cases with cryptic molecular translocation have RUNX1T1 (runt-related transcription been detected --> FISH use may be relevant. factor 1; translocated to, 1 (cyclin D- Additional anomalies related)) Sole anomaly in only 20-30%; additional anomalies: Location loss of Y or X chromosome in half cases (1 X must 8q21.3 be present), del(7q) or -7, +8, del (9q): 10% each. DNA/RNA Variants Transcription is from telomere to centromere. Complex t(8;21;Var) involving a (variable) third Protein chromosome have been described in 3%; part from 3 proline rich domains, 2 Zn fingers, and in C-term, chromosome 21 goes on der(8), part of the 8 on der a PEST region; tissue restricted expression; nuclear (Var), and part of Var on der(21); therefore, the localisation; putative transcription factor. crucial event lies on der(8).

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t(8;21)(q22;q22) RUNX1/RUNX1T1 Kroes W, Stevens-Kroef M

RUNX1 (runt-related transcription Oncogenesis factor 1 (acute myeloid leukemia 1; Probable altered transcriptional regulation of normal aml1 oncogene)) RUNX1 target genes. Location References 21q22.12 Acute myelogenous leukemia with an 8;21 translocation. A DNA/RNA report on 148 cases from the Groupe Français de Transcription is from telomere to centromere. Cytogénétique Hématologique. Cancer Genet Cytogenet. 1990 Feb;44(2):169-79 Protein Contains a Runt domain and, in the C-term, a Berger R, Bernheim A, Daniel MT, Valensi F, Sigaux F, Flandrin G. Cytologic characterization and significance of transactivation domain; forms heterodimers; widely normal karyotypes in t(8;21) acute myeloblastic leukemia. expressed; nuclear localisation; transcription factor Blood. 1982 Jan;59(1):171-8 (activator) for various hematopoietic-specific genes. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson Result of the chromosomal RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield anomaly CD. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert Hybrid gene panel, on behalf of the European LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74 Description Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, 5' RUNX1 - 3' RUNX1T1; breakpoints: at the very Sakurai M, Kaneko Y. The 8;21 chromosome translocation 5' end of RUNX1T1, between exons 5 and 6 in in acute myeloid leukemia is always detectable by molecular RUNX1. analysis using AML1. Blood. 1993 Mar 15;81(6):1573-9 Detection Nucifora G, Rowley JD. AML1 and the 8;21 and 3;21 Karyotyping, RT-PCR and FISH for cases of typical translocations in acute and chronic myeloid leukemia. Blood. 1995 Jul 1;86(1):1-14 cell morphology, but apparently without the t(8;21); RT-PCR for minimal residual disease detection Ohki M. Molecular basis of the t(8;21) translocation in acute myeloid leukaemia. Semin Cancer Biol. 1993 Dec;4(6):369- Fusion protein 75 Description Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, The N-term runt domain from RUNX1 is fused to the Stein H, Thiele J, Vardiman JW.. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th 577 C-term residues from RUNX1T1; reciprocal Edition; Lyon, France: IARC Press; 2008. product not detected; probable DNA binding role; the fusion protein retains the ability to recognize the This article should be referenced as such: RUNX1 concensus binding site (--> negative Kroes W, Stevens-Kroef M. t(8;21)(q22;q22) dominant competitor with the normal RUNX1) and RUNX1/RUNX1T1. Atlas Genet Cytogenet Oncol to dimerize with the CBFb subunit. Haematol. 2017; 21(2):52-55.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 55 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Leukaemia Section Short Communication t(8;14)(q24;q32) / t(2;8)(p12;q24) / t(8;22)(q24;q11) Eva van den Berg, Marian Stevens-Kroef Department of Genetics, University Medical Centre Groningen, Groningen; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Published in Atlas Database: May 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0814ID1050.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68159/05-2016-t0814ID1050.pdf DOI: 10.4267/2042/68159 This article is an update of : Bilhou-Nabera, C. 8;14)(q24;q32) - t(2;8)(p12;q24) - t(8;22)(q24;q11). Atlas Genet Cytogenet Oncol Haematol. 1999;3(2) 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 Identity Review on t(8;14)(q24;q32) / t(2;8)(p12;q24) / Note t(8;22)(q24;q11), with data on clinics, and the genes The 3 translocations are variants of each other, and involved. they share the same clinical significance.

Top row: t(2;8)(p12;q24) G- banding - Courtesy Diane H.Norback, Eric B. Johnson, Sara Morrison-Delap; R- banding - (middle right) Courtesy Jean-Luc Lai; (right) Courtesy Hossein Mossafa; below: Courtesy Roland Berger. Middle rows: t(8;14)(q24;q32) G- banding - (left, middle left, center) Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap; R- banding - middle right Courtesy Jean-Luc Lai; right: Jean Loup Huret; below: Courtesy Roland Berger. Lower row: t(8;22)(q24;q11) G- banding (left and center) - Courtesy Diane H. Norback, Eric B.Johnson, Sara Morrison-Delap UW Cytogenetic Services; R- banding - (right) Courtesy Jacques Boyer.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 56 t(8;14)(q24;q32) / t(2;8)(p12;q24) / t(8;22)(q24;q11) van den Berg E, Stevens-Kroef M

Bone marrow sample: the medium-sized cells show a diffuse monotonous pattern of infiltration. The nuclei are round, cytoplasm deeply basophilic and usually contain vacuoles. The morphological feature in this bone marrow smear (Giemsa), quite similar to tumor cells as seen in tissue imprints, is highly characteristic of Burkitt lymphoma - Text and iconography Courtesy Georges Flandrin 2005.

Clinics and pathology Cytology ALL : L3 morphology according to the FAB Disease classification, very occasionally L1 or L2 cytology described both in B-cell acute lymphoblastic reported. leukemia (ALL) and in non-Hodgkin lymphomas (NHL), especially in the Burkitt lymphoma , and Cytogenetics 'double-hit' diffuse large B-cell lymphomas (DLBCL). Phenotype/cell stem origin The postulated normal counterpart is the germinal centre or post-germinal centre B-cell. Epidemiology Most Burkitt lymphoma cases show the t(8;14)(q24;q32) MYC/IGH and less commonly the t(8;22)(q24;q11) or t(2;8)(p12;q24). The translocation is present in both the endemic African The figure illustrates the translocation of the c-Myc gene Burkitt lymphoma and in the non endemic tumor (probe 944B18, red) to 14q32.3 - Courtesy Mariano Rocchi. type (Europe, America, and Japan). In case the Cytogenetics morphological Burkitt lymphoma infiltrated the bone marrow t(8;14) is described in 75-85% of the cases, t(2;8) in (leukemic phase) the MYC-translocation can be 5%, and t(8 ;22) in the remaining 10%; high-quality demonstrated in the bone marrow or blood as well. metaphases are required to detect t(8;14) and t(8;22). If no immunophenotyping results are available, it is good practice to exclude a BCL2 rearrangement Additional anomalies because a t(8;14) can be observed in other B cell Reported in 70% cases in Burkitt lymphoma and neoplasms (such as double hit DLBCL see below). DLBCL, especially: t(14;18)(q32;q21) in double-hit Some DLBCL ('double-hit') cases contain the t(8;14) DLBCL lymphoma's, structural rearrangements of translocation. In some clinical studies patients with the long arm of chromosome 1 (30% cases) resulting DLBCL and MYC rearrangement will receive more in a partial trisomy 1q, rearrangements of 13q34 aggressive treatment. The disease defines the (15% cases). prognosis. Given the correct treatment regime Burkitt lymphoma patients do well, while the Variants outcome in double-hit DLBCL patient is totally t(2;8)(p12;q24) and t(8;22)(q24;q11) are variants of different.

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t(8;14)(q24;q32) / t(2;8)(p12;q24) / t(8;22)(q24;q11) van den Berg E, Stevens-Kroef M

the t(8;14)(q24;q32); three-way rearrangements and Immunoglobulin genes: translocations of submicroscopic chromosome fragments have also been described IGH, IGK, IGL Location Genes involved and in 14q32, 2p12 and 22q11 respectively. proteins Result of the chromosomal Note On the molecular point of view, in all these three anomaly translocations, the oncogene C-MYC is juxtaposed Hybrid gene either with the immunoglobulin heavy chain locus IGH (14q32), the kappa light-chain locus IGK Note (2p12), or the lambda light-chain locus IGL (22q11); No hybrid transcript. all these translocations share a breakpoint in 8q24 The translocation leads to the MYC gene under (C-MYC locus). The MYC breakpoints are diverse direct regulation of the enhancer of the IGH (or and distributed over a 2Mb region. Therefore it has IGK/IGL genes), thereby causing high level to be noted that not all MYC-rearrangements can be transcription of the MYC gene. detected by FISH. Description MYC MYC is translocated to der(14) in the t(8;14), Location whereas it remains on der(8) in the variant translocations; t(8;14) leads to a head-to-head fusion 8q24 of MYC with the heavy chain immunogloulin locus DNA/RNA : 8q24 is close to the 5' extremity of C-MYC exon 2, The human C-MYC oncogene is the cellular leading the all translated gene region to 14q32; the homologue of an avian retrovirus; in vertebrates, it 8q24 breakpoint region is variable, scattered over a belongs to a small gene family with closely related 190 Kb region, 5' far from MYC or within MYC; the members (MYC, N-MYCN, MYCL); C-MYC has 14q32 breakpoint region is mainly located in the three exons; two promoters P1 and P2 control the C- constant region, very close within the switch or MYC transcription; the choice of the promoter joining regions; MYC juxtaposed to the depends on the myc protein level. P2 promoter is immunoglobin constant regions and enhancer is considered as the most active promoter, generating a overexpressed, shutting down the normal remaining 2.25 kb transcript, whereas P1 promoter enrates a 2.4 MYC; in both t(2;8) and t(8;22), the breakpoint is in kb transcript; the main part of 5' first exon 3' of or distal to the MYC gene which always corresponds to an untranslated region, MYC1 remains on der(8); the rearrangement with translation starting at a CUG codon near its 3'end, respectively Igk or Igl and C-MYC is head-to-tail. having 14 additional N-terminal amino-acids compared with MYC2 translation site localized 5' Fusion protein near the second exon beginning Note Protein The protein MYC resulting from the translation of Myc protein is a transcription factor of the helix- the second and third exons, through DNA-binding loop-helix/leucine zipper family that activates properties, plays a role in regulating cell growth and transcription as obligate heterodimer with a partner differentiation protein, MAX.

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t(8;14)(q24;q32) / t(2;8)(p12;q24) / t(8;22)(q24;q11) van den Berg E, Stevens-Kroef M

Oncogenesis Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of Constitutive expression of c-myc induces the hematopoietic and lymphoid tissues: report of the proliferation even in the absence of growth factors. Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999 Dec;17(12):3835-49 To be noted Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Case Report Nader A, Ott G, Müller-Hermelink K, Feller A, Heinz R. Translocation t(8;14)(q24;q32) as a clue for the Clinicopathogenetic significance of chromosomal diagnosis of B cell prolymphocytic leukemia abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group. Blood. References 1999 Nov 1;94(9):3114-20 Hecht JL, Aster JC. Molecular biology of Burkitt's Kornblau SM, Goodacre A, Cabanillas F. Chromosomal lymphoma. J Clin Oncol. 2000 Nov 1;18(21):3707-21 abnormalities in adult non-endemic Burkitt's lymphoma and leukemia: 22 new reports and a review of 148 cases from Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, the literature. Hematol Oncol. 1991 Mar-Apr;9(2):63-78 Stein H, Thiele J, Vardiman JW. Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th Edition; Longo DL, Duffey PL, Jaffe ES, Raffeld M, Hubbard SM, Lyon, France: IARC Press; 2008. Fisher RI, Wittes RE, DeVita VT Jr, Young RC. Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: a high- This article should be referenced as such: grade lymphoma responsive to ProMACE-based van den Berg E, Stevens-Kroef M. t(8;14)(q24;q32) combination chemotherapy. J Clin Oncol. 1994 IGH/MYC; t(2;8)(p12;q24) IGK/MYC; t(8;22)(q24;q11) Oct;12(10):2153-9 IGL/MYC). Atlas Genet Cytogenet Oncol Haematol. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller- 2017; 21(2):56-59.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 59 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Leukaemia Section Short Communication

Anaplastic large cell lymphoma, ALK-negative Rebecca L Boddicker, Andrew L Feldman Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. [email protected] (RLB); [email protected] (ALF)

Published in Atlas Database: May 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ALCLALKnegID1705.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68160/05-2016-ALCLALKnegID1705.pdf DOI: 10.4267/2042/68160 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

Males are affected more commonly than females Abstract (M:F, ~1.5:1). Review on Anaplastic large cell lymphoma, ALK- Clinics negative, with data on clinics, and the genes Patients with ALCL, ALK-negative typically present involved. with lymphadenopathy, often with stage III/IV Keywords disease, and B symptoms (ten Berge, de Bruin et al. Anaplastic large cell lymphoma, ALK-negative 2003). Extranodal sites also may be involved, including skin, bone, and soft tissues. Secondary cutaneous involvement by ALCL, ALK-negative Clinics and pathology must be distinguished from primary cutaneous Disease ALCL, which is a distinct entity (Bekkenk, Geelen et al. 2000). Anaplastic large cell lymphoma (ALCL), ALK- negative is a CD30-positive T-cell non-Hodgkin Pathology lymphoma that by definition resembles ALCL, By definition, the morphologic appearance is similar ALK-positive but lacks ALK expression (Mason, to that seen in ALCL, ALK-positive (Mason, Harris Harris et al. 2008). et al. 2008). Specifically, most cases resemble the ALCL, ALK-negative was classified as a provisional so-called "common" pattern of ALK, ALK-positive entity distinct from ALCL, ALK-positive in the 2008 and show sheet-like growth of tumor cells, WHO classification, and is anticipated to be sometimes sparing residual lymphoid follicles upgraded to a definite entity in the 2016 WHO (Delsol, Falini et al. 2008). Sinusoidal involvement update (Swerdlow, Campo et al. 2016). is common, and cohesive clusters of intrasinusoidal tumor cells may mimic metastatic carcinoma. The Etiology tumor cells typically are large and may show The etiology of ALCL, ALK negative is unknown. significant pleomorphism. So-called "hallmark" cells, with horseshoe-shaped or reniform nuclei, Epidemiology always can be identified (Benharroch, Meguerian- ALCL, ALK-negative makes up between 2.6% and Bedoyan et al. 1998). Immunophenotyping studies 9.4% of T-/NK-cell non-Hodgkin lymphomas, with are essential to the diagnosis of ALCL, ALK- the lowest proportion occurring in Asia and the negative. All cases express CD30 by definition. highest in Europe (Vose, Armitage et al. 2008). Aberrant loss of pan-T-cell antigen expression is ALCL, ALK-negative generally occurs in older common, and about two-thirds of cases express patients, with a median age of diagnosis of 55-60 cytotoxic proteins (TIA1, granzyme B, or perforin) years, compared to 25-35 years for ALK-positive (Savage, Harris et al. 2008). ALK protein is absent. ALCL (Ferreri, Govi et al. 2013).

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 60 Anaplastic large cell lymphoma, ALK-negative Boddicker RL, Feldman AL

ALCL, ALK-negative. The tumor is composed of sheets of large pleomorphic cells, some with horseshoe-shaped nuclei ("hallmark" cells; H&E, top). By immunohistochemical stains the tumor cells are negative for the B-cell marker, CD20; positive for the T-cell marker, CD3; positive for CD30; and negative for ALK.

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Anaplastic large cell lymphoma, ALK-negative Boddicker RL, Feldman AL

Treatment Gene fusions involving tyrosine kinase genes other than ALK have been reported in ALCL, ALK- ALCL, ALK-negative is typically treated with negative, including TYK2 (t(10;19)(q24;p13) CHOP (cyclophosphamide, doxorubicin, vincristine, (NFKB2/TYK2), t(1;19)(p34;p13) and prednisone) or CHOP-like chemotherapy, often (PABPC4/TYK2) and ROS1 (t(6;10)(q22;q24) followed by autologous stem cell transplantation (NFKB2/ROS1), (NCOR2/ROS1)(Crescenzo, (Bennani-Baiti, Ansell et al. 2016). New targeted Abate et al. 2015). agents such as brentuximab vedotin and histone deacetylase inhibitors have demonstrated efficacy in relapsed and refractory disease. References

Prognosis Bekkenk MW, Geelen FA, van Voorst Vader PC, Heule F, The prognosis for ALCL, ALK-negative is poorer Geerts ML, van Vloten WA, Meijer CJ, Willemze R. Primary and secondary cutaneous CD30(+) lymphoproliferative than for ALCL, ALK-positive, with a 5-year overall disorders: a report from the Dutch Cutaneous Lymphoma survival (OS) rate of 49% compared to 70% for the Group on the long-term follow-up data of 219 patients and latter (Savage, Harris et al. 2008). However, guidelines for diagnosis and treatment. Blood. 2000 Jun prognosis is better than for most other types of T-cell 15;95(12):3653-61 non-Hodgkin lymphomas, including peripheral T- Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, cell lymphoma, not otherwise specified (PTCL, Brugières L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G. ALK-positive NOS). Recent data have shown that ALCL, ALK- lymphoma: a single disease with a broad spectrum of negative is a genetically heterogeneous disease, and morphology. Blood. 1998 Mar 15;91(6):2076-84 that outcomes vary widely based on genetic subtype Bennani-Baiti N, Ansell S, Feldman AL. Adult systemic (Parrilla Castellar, Jaffe et al. 2014). Specifically, 5- anaplastic large-cell lymphoma: recommendations for year OS was very good (90%) in patients carrying diagnosis and management. Expert Rev Hematol. DUSP22 rearrangements, poor (17%) in TP63/ - 2016;9(2):137-50 rearranged cases, and intermediate (42%) in patients Boi M, Rinaldi A, Kwee I, Bonetti P, Todaro M, Tabbò F, lacking ALK/, DUSP22, and TP63 rearrangements. Piva R, Rancoita PM, Matolcsy A, Timar B, Tousseyn T, Rodríguez-Pinilla SM, Piris MA, Beà S, Campo E, Bhagat G, Swerdlow SH, Rosenwald A, Ponzoni M, Young KH, Genetics Piccaluga PP, Dummer R, Pileri S, Zucca E, Inghirami G, Recurrent somatic mutations in the JAK1/ and/or Bertoni F. PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood. 2013 Oct STAT3/ genes have been reported in 18% of ALCL, 10;122(15):2683-93 ALK-negative (Crescenzo, Abate et al. 2015). JAK1 Crescenzo R, Abate F, Lasorsa E, Tabbo' F, Gaudiano M, mutations were most commonly G1097D/S, while Chiesa N, Di Giacomo F, Spaccarotella E, Barbarossa L, STAT3 mutations included Y640F, N647I, D661Y, Ercole E, Todaro M, Boi M, Acquaviva A, Ficarra E, Novero and A662V. D, Rinaldi A, Tousseyn T, Rosenwald A, Kenner L, Cerroni L, Tzankov A, Ponzoni M, Paulli M, Weisenburger D, Chan WC, Iqbal J, Piris MA, Zamo' A, Ciardullo C, Rossi D, Cytogenetics Gaidano G, Pileri S, Tiacci E, Falini B, Shultz LD, Mevellec L, Vialard JE, Piva R, Bertoni F, Rabadan R, Inghirami G. Cytogenetics morphological Convergent mutations and kinase fusions lead to oncogenic Copy number losses involving PRDM1 (6q21) STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015 Apr 13;27(4):516-32 and/or TP53/ (17p13) are recurrent in ALCL, ALK- negative, and have been associated with poor Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: survival (Boi, Rinaldi et al. 2013). pathology findings and clinical outcomes. J Clin Oncol. 2008 Recurrent chromosomal rearrangements involving Sep 1;26(25):4124-30 the DUSP22 -IRF4/ locus on 6p25.3 are present in Delsol, G., B. Falini, et al.. Anaplastic large cell lymphoma, ~30% of ALCL, ALK-negative (Feldman, Law et al. ALK-positive. WHO Classification of Tumours of 2009; Feldman, Dogan et al. 2011; Parrilla Castellar, Haematopoietic and Lymphoid Tissues. International Jaffe et al. 2014). The most common partner is a Agency for Research on Cancer: (2008) 312-316. non-genic region on 7q32.3. DUSP22 Feldman AL, Law M, Remstein ED, Macon WR, Erickson rearrangements are associated with decreased LA, Grogg KL, Kurtin PJ, Dogan A. Recurrent translocations expression of the dual-specificity phosphatase gene, involving the IRF4 oncogene locus in peripheral T-cell DUSP22; lack of cytotoxic marker expression; lymphomas Leukemia 2009 Mar;23(3):574-80 favorable prognosis; and distinct morphologic King RL, Dao LN, McPhail ED, Jaffe ES, Said J, Swerdlow features (King, Dao et al. 2016). SH, Sattler CA, Ketterling RP, Sidhu JS, Hsi ED, Karikehalli S, Jiang L, Gibson SE, Ondrejka SL, Nicolae A, Macon WR, Rearrangements involving TP63, most often Dasari S, Parrilla Castellar E, Feldman AL. Morphologic partnering with TBL1XR1/ occur in ~8% of ALCL, Features of ALK-negative Anaplastic Large Cell ALK-negative and have been associated with poor Lymphomas With DUSP22 Rearrangements Am J Surg prognosis (Vasmatzis, Johnson et al. 2012; Parrilla Pathol 2016 Jan;40(1):36-43 Castellar, Jaffe et al. 2014).

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Vose J, Armitage J, Weisenburger D; International T-Cell International Peripheral T-Cell Lymphoma Project Blood Lymphoma Project. International peripheral T-cell and 2008 Jun 15;111(12):5496-504 natural killer/T-cell lymphoma study: pathology findings and clinical outcomes J Clin Oncol 2008 Sep 1;26(25):4124-30 Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Delsol, G., B. Falini, et al.. Anaplastic large cell lymphoma, Jaffe ES. The 2016 revision of the World Health ALK-positive. WHO Classification of Tumours of Organization classification of lymphoid neoplasms Blood Haematopoietic and Lymphoid Tissues. International 2016 May 19;127(20):2375-90 Agency for Research on Cancer: (2008) 312-316. Vasmatzis G, Johnson SH, Knudson RA, Ketterling RP, Mason, D. Y., N. L. Harris, et al.. Anaplastic large cell Braggio E, Fonseca R, Viswanatha DS, Law ME, Kip NS, lymphoma, ALK-negative. WHO Classification of Tumours Ozsan N, Grebe SK, Frederick LA, Eckloff BW, Thompson of Haematopoietic and Lymphoid Tissues. S. Swerdlow, E. EA, Kadin ME, Milosevic D, Porcher JC, Asmann YW, Smith Campo, N. Harris et al. Lyon, International Agency for DI, Kovtun IV, Ansell SM, Dogan A, Feldman AL. Genome- Research on Cancer: (2008) 317-319. wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell Parrilla Castellar ER, Jaffe ES, Said JW, Swerdlow SH, lymphomas Blood 2012 Sep 13;120(11):2280-9 Ketterling RP, Knudson RA, Sidhu JS, Hsi ED, Karikehalli S, Jiang L, Vasmatzis G, Gibson SE, Ondrejka S, Nicolae Vose J, Armitage J, Weisenburger D; International T-Cell A, Grogg KL, Allmer C, Ristow KM, Wilson WH, Macon WR, Lymphoma Project. International peripheral T-cell and Law ME, Cerhan JR, Habermann TM, Ansell SM, Dogan A, natural killer/T-cell lymphoma study: pathology findings and Maurer MJ, Feldman AL. ALK-negative anaplastic large cell clinical outcomes J Clin Oncol 2008 Sep 1;26(25):4124-30 lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes Blood 2014 Aug ten Berge RL, de Bruin PC, Oudejans JJ, Ossenkoppele GJ, 28;124(9):1473-80 van der Valk P, Meijer CJ. ALK-negative anaplastic large- cell lymphoma demonstrates similar poor prognosis to Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, peripheral T-cell lymphoma, unspecified Histopathology Connors JM, Rimsza L, Pileri SA, Chhanabhai M, Gascoyne 2003 Nov;43(5):462-9 RD, Armitage JO, Weisenburger DD; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large- This article should be referenced as such: cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell Boddicker RL, Feldman AL. Anaplastic large cell lymphoma, not otherwise specified: report from the lymphoma, ALK-negative. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2):60-63.

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Leukaemia Section Short Communication

Pediatric-type Follicular Lymphoma Michael G. Ozawa, Robert S. Ohgami Department of Pathology, Stanford University, Stanford, CA, USA. [email protected]

Published in Atlas Database: May 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/PediatrFLID1749.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68161/05-2016-PediatrFLID1749.pdf DOI: 10.4267/2042/68161 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 Epidemiology Review on Pediatric-type Follicular Lymphoma with Pediatric-type follicular lymphoma is a rare disease data on clinics, and the genes involved. with incidence estimates of approximately 5% of all childhood lymphomas (O'Suoji et al., 2016). The age Clinics and pathology of presentation is between the ages of 3 and 18 years of age, though cases observed in early adulthood Disease have also been described. A male predominance is commonly seen. Pediatric-type follicular lymphoma (pFL), which was formerly a provisional diagnosis under follicular Clinics lymphoma, is a newly recognized entity in the 2016 pFL typically is localized to lymph nodes within the WHO classification (Swerdlow et al., 2016). It is an cervical region although extranodal sites including extremely rare nodal B-cell lymphoma occurring the testis, epididymis and gastrointestinal tract do predominantly in the pediatric and young-adult occur. The vast majority of patients present with population, which shows unique characteristics localized involvement without systemic disease and distinct from the more common follicular lymphoma follow an indolent clinical course. seen in adults (Louissaint et al., 2012). Pathology Phenotype/cell stem origin Histologically, lymph nodes show effacement of pFL is a proliferation of follicle center B-cells with normal architecture by a proliferation of expansile, often blastoid morphologic features. The B-cells ill-defined follicles with attenuated mantle zones typically express markers of germinal center B-cells, (figure 1). The atypical follicles are comprised of a including CD10, BCL6, human germinal center- mixture of intermediate and larger-sized associated lymphoma (HGAL) and Lim domain only centroblastic lymphocytes with more immature 2 (LMO2) (Liu et al., 2013; Karnik et al., 2015). The chromatin often lending to an interpretation of neoplastic cells largely lack BCL2 protein higher-grade cytology and aggressive disease. expression, or if it is expressed show only dim or Notably, these morphologic features are often not partial expression. Importantly, the characteristic entirely specific and can show overlap with other IGH - BCL2 t(14;18)(q32;q21) translocation, seen in lymphomas including pediatric marginal zone follicular lymphomas of adults, is absent. The lymphoma (Quintanilla-Martinez et al., 2016). By proliferation index is elevated (>30%) as assessed by the 2016 WHO classification, diffuse areas Ki67. suggesting progression or transformation, exclude a diagnosis of pFL.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 64 Pediatric-type Follicular Lymphoma Ozawa MG, Ohgami RS

Figure 1: Morphologic features of pediatric-type follicular lymphoma. Irregularly shaped enlarged follicles with abnormal mantle zones are seen at low power (40X). High power magnification illustrates the cytomorphology of neoplastic cells which have more blastoid chromatin and irregular nuclear contours, inset (1000X).

Treatment Cytogenetics Patients presenting with localized disease respond to surgical resection without further intervention. Cytogenetics morphological Historically, additional management strategies have Recurrent cytogenetic abnormalities are not included surgical excision with chemotherapy with common in pFL. BCL2, BCL6, and MYC or without local radiation (Attarbaschi et al., 2013). rearrangements are absent. Recurrent deletion or copy number-neutral loss of heterozygosity (LOH) Prognosis at 1p36 have been described, and these alterations Prognosis is similar to other indolent lymphomas, are associated with TNFRSF14 mutations (Martin- with excellent progression free and overall survival. Guerrero et al., 2013). The vast majority of patients achieve complete remission and show no evidence of disease Cytogenetics molecular following local surgical treatment or radiation The mutational landscape of pFL is not well therapy. understood. TNFRSF14 mutations have been

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Pediatric-type Follicular Lymphoma Ozawa MG, Ohgami RS

reported in association with, as well as distinct from 1p36 deletion or copy number neutral LOH. References Recently, a recurrent somatic variant encoding Attarbaschi A, Beishuizen A, Mann G, Rosolen A, Mori T, p.Lys66Arg in the transcription factor interferon Uyttebroeck A, Niggli F, Csoka M, Krenova Z, Mellgren K, Kabickova E, Chiang AK, Reiter A, Williams D, Burkhardt B. regulatory factor 8 (IRF8) was described in 3 of 6 Children and adolescents with follicular lymphoma have an cases of pFL (50%) by whole exome deep excellent prognosis with either limited chemotherapy or with sequencing (Ozawa et al., 2016). This point a "Watch and wait" strategy after complete resection. Ann mutation was not observed in adult follicular Hematol. 2013 Nov;92(11):1537-41 lymphoma or cases of pediatric marginal zone Karnik T, Ozawa MG, Lefterova M, Luna-Fineman S, lymphoma. Alvarez E, Link M, Zehnder JL, Arber DA, Ohgami RS. The utility of IgM, CD21, HGAL and LMO2 in the diagnosis of pediatric follicular lymphoma. Hum Pathol. 2015 Genes involved and Apr;46(4):629-33 proteins Liu Q, Salaverria I, Pittaluga S, Jegalian AG, Xi L, Siebert R, Raffeld M, Hewitt SM, Jaffe ES. Follicular lymphomas in Note children and young adults: a comparison of the pediatric While the underlying genetics driving pFL are under variant with usual follicular lymphoma. Am J Surg Pathol. 2013 Mar;37(3):333-43 investigation, recent studies have suggested at least two potential pathogenic pathways. Louissaint A Jr, Ackerman AM, Dias-Santagata D, Ferry JA, Hochberg EP, Huang MS, Iafrate AJ, Lara DO, Pinkus GS, TNFRSF14 (TNF receptor superfamily Salaverria I, Siddiquee Z, Siebert R, Weinstein HJ, Zukerberg LR, Harris NL, Hasserjian RP. Pediatric-type member 14) nodal follicular lymphoma: an indolent clonal proliferation in Location children and adults with high proliferation index and no 1p36.32 BCL2 rearrangement. Blood. 2012 Sep 20;120(12):2395- 404 Note Martin-Guerrero I, Salaverria I, Burkhardt B, TNFRSF14 is a member of the TNF (tumor necrosis Szczepanowski M, Baudis M, Bens S, de Leval L, Garcia- factor) receptor superfamily. In T-cells it is involved Orad A, Horn H, Lisfeld J, Pellissery S, Klapper W, Oschlies in signal transduction pathways that activate I, Siebert R. Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation inflammatory and inhibitory immune responses. The negative pediatric follicular lymphomas. Haematologica. role of TNFRSF14 in normal B-cell physiology is 2013 Aug;98(8):1237-41 unclear, but it is known to be recurrently deleted or O'Suoji C, Welch JJ, Perkins SL, Smith LM, Weitzman S, show copy number-neutral loss of heterozygosity Simko SJ, Galardy PJ, Bollard CM, Gross TG, Termuhlen (LOH) along with somatic point mutations in cases AM. Rare Pediatric Non-Hodgkin Lymphomas: A Report of pFL. From Children's Oncology Group Study ANHL 04B1. Pediatr Blood Cancer. 2016 May;63(5):794-800 IRF8 (interferon regulatory factor 8) Ozawa MG, Bhaduri A, Chisholm KM, Baker SA, Ma L, Location Zehnder JL, Luna-Fineman S, Link MP, Merker JD, Arber 16q24.1 DA, Ohgami RS. A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal Note marginal zone lymphoma. Mod Pathol. 2016 IRF8 is a member of the IRF family of transcription Oct;29(10):1212-20 factors contributing to hematopoietic cellular Quintanilla-Martinez L, Sander B, Chan JK, Xerri L, Ott G, differentiation and development, cell cycle Campo E, Swerdlow SH. Indolent lymphomas in the regulation and apoptosis. Variants in this gene have pediatric population: follicular lymphoma, IRF4/MUM1+ lymphoma, nodal marginal zone lymphoma and chronic been recently reported in a small percentage of adult lymphocytic leukemia. Virchows Arch. 2016 follicular lymphomas and pediatric-type follicular Feb;468(2):141-57 lymphomas. In pediatric-type follicular lymphoma Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, the mutations are a specific recurrent mutation, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, p.Lys66Arg, different from mutations in IRF8 which Jaffe ES. The 2016 revision of the World Health are seen in adult follicular lymphomas (Ozawa et al., Organization classification of lymphoid neoplasms. Blood. 2016). While currently little is known about the 2016 May 19;127(20):2375-90. pathogenic role of IRF8 in this setting, the This article should be referenced as such: significant portion of pediatric-type follicular lymphomas with the same recurrent nucleotide Ozawa MG, Ohgami RS. Pediatric-type Follicular Lymphoma. Atlas Genet Cytogenet Oncol Haematol. change is highly suggestive of a critical alteration 2017; 21(2):64-66. and potential unique disease origin.

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Leukaemia Section Short Communication

Plasmablastic lymphoma (PBL) Aurelia Meloni-Ehrig, Lawrence Hertzberg CSI Laboratories, Alpharetta, GA / e-Mail: [email protected]

Published in Atlas Database: May 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/PlasmablasticLymphomaID1564.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68162/05-2016-PlasmablasticLymphomaID1564.pdf DOI: 10.4267/2042/68162 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

associated with HIV infection and EBER positivity, Abstract whereas PCM patients present with monoclonal Review on plasmablastic lymphoma, with data on paraproteinemia, hypercalcemia, renal dysfunction, clinics, and the genes involved. and lytic bone lesions. For cases that continue to be Keywords indistinguishable based on immunophenotypic and clinical findings, the presence of a MYC (8q24.2) plasmablastic lymphoma translocation, which tends to occur in most PBL patients, might be used as a marker in the Clinics and pathology identification of PBL (Taddesse-Heath et al., 2010). Disease Epidemiology Phenotype/cell stem origin PBL is a rare aggressive B-cell lymphoma strongly associated with HIV infection. It makes up The cell of origin involved in plasmablastic approximately 2% of all HIV-related lymphomas. lymphoma (PBL) is the plasmablast. The current According to a recent study (Castillo et al., 2015), belief is that the plasmablast is derived from a post- over 600 patients with this lymphoma have been germinal center B-cell that has undergone reported in a period of 15 years. The majority of preterminal differentiation via somatic these patients (63%) were HIV-positive and 28% hypermutation and class switching recombination to were HIV-negative. Furthermore, according to the resemble a plasma cell rather than a B-cell (Castillo Castillo and co-authors report, 3% of PBL arose et al., 2008; Hsi et al. 2011). The plasma cell markers from preexisting lymphoproliferative neoplasm via VS38c, CD38, multiple myeloma oncogene-1 transformation, and about 6% arose in patients that (MUM1), and CD138 (syndecan-1) seem to be had undergone solid organ transplant. The disease is almost universally expressed in PBL. There is little more common in males than females (4;1). PBL is to no expression of the leukocyte common antigen reported to occur at all ages but is very rare in (CD45) or the B-cell markers CD20, CD79a, and children (approximately 3% of all reported cases PAX5. However, there is some distinction in the were children, for the most part HIV-positive immunophenotype between HIV-positive and HIV- patients). negative patients with PBL. HIV-positive patients seem to show a greater expression of CD20 and Clinics CD56 compared to HIV-negative patients (Folk et There are differences in the clinical presentation of al., 2006). The immunophenotypic similarities PBL in patients with and without HIV infection. between PBL and plasmablastic or anaplastic plasma First of all, the majority of patients with PBL are cell myeloma (PCM) might be challenging for the HIV-positive male patients. Interestingly, most diagnosis (Vega et al., 2005). Therefore, it is female patients with PBL do not have HIV, in sharp important to look carefully at additional features that contrast with the male population (Morscio et al., are unique and might help in differentiating these 2 2008). neoplasms. It should be noted that PBL is strongly

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 67 Plasmablastic lymphoma (PBL) Meloni-Ehrig A, Hertzberg L

Fig.1. Hematoxylin and eosin stained section. The malignant cells are large, with clumped chromatin, smooth nuclear contours, and eccentric cytoplasm (plasmacytic appearance). Occasionally, a single prominent "cherry red" nucleolus might be seen in these cells.

Most of the HIV-positive patients present with resemble differentiated plasma cells with larger extranodal disease particularly affecting the oral nuclei and basophilic cytoplasm (Hsi et al. 2011). cavity (Delecluse et al., 1997; Cattaneo et al., 2005), Occasional "cherry red" nucleolus might be seen in followed by the gastrointestinal tract (Luria et al., the plasmablasts. The typical surface markers of 2014), and skin (Jambusaria et al., 2008). mature B cells, such as CD20 and CD45, are usually Furthermore, most patients in this group present with down regulated in these cells. Similarly, PAX5 and advanced clinical stage (stages III or IV) with BCL6 are also down regulated. Instead, these cells frequent bone marrow involvement. Patients without now express cells surface markers typically HIV develop PBL at an older age (median age: 55 expressed by plasma cells, i.e., VS38c, CD38, years) than the HIV-positive patients (median age: multiple myeloma oncogene-1 (MUM1), and CD138 42 years). PBL of non-immunocompromized (syndecan-1). patients is more variable as far as sites of Prognosis involvement. However, the oral cavity is still the most common presentation. Advanced clinical stage The prognosis of patients with PBL is poor with a and bone marrow involvement is less common in this median overall survival (OS) between 8 and 15 group than in the immunocompromized individuals months (Castillo et al., 2008). Specifically, the (Morscio et al., 2014). PBL has been reported to median OS for HIV-positive patients is on average occur also in solid organ post-transplant patient. The 10 months, for HIV-negative immunocompetent is majority of these patients received a transplant of the on average 11 months, and for post-transplant heart, followed by the kidney, hematopoietic stem patients is on average 7 months (Morscio 2014). cell, lung, liver, and pancreas. Sites of involvement According to the International Prognostic Index (IPI) in this group of patients typically are the lymph scoring system for aggressive lymphoma, several nodes, followed by the skin. Approximately 50% of factors affect the prognosis and survival, such as age, these patients had advanced stage disease (Morscio performance status, LDH levels, bone marrow et al., 2014). involvement, number of extranodal sites, and clinical stage. Studies, however, are controversial on which Cytology factor(s) play a bigger part in the prognosis of PBL. The cells involved in PBL are the plasmablasts, Some researchers in this field indicated that age, which are large cells characterized by abundant LDH levels, and bone marrow involvement do not cytoplasm and prominent nucleoli similar to large affect outcomes (Castillo et al., 2012), whereas other immunoblasts. The plasmablasts features are investigators found that age, LDH levels, and Ki-67 particularly evident in the oral mucosa of HIV- levels ≥80% were the main factors associated with positive patients. On the other hand, when PBL adverse outcomes (Schommers et al., 2013). occurs in HIV-negative patients, the neoplastic cells Furthermore, HIV-positive patients with a MYC

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Plasmablastic lymphoma (PBL) Meloni-Ehrig A, Hertzberg L

translocation have been found to have a very short seem to occur at similar frequency as opposed to OS (Taddesse-Heath et al., 2010; Castillo et al., Burkitt lymphoma where the most common IG- 2012). Treatment seems to ameliorate the outcome MYC translocation is the t(8;14)/IGH-MYC, versus patients that receive no treatment at all. followed by t(8;22)/IGL-MYC and t(2;8)/IGK- However, currently, the use of cyclophosphamide, MYC. doxorubicin, vincristine and prednisone (CHOP) is The IG/MYC translocations in PBL are frequently considered an inadequate therapy, and current associated with EBV infection particularly in guidelines recommend more intensive regimens endemic and immunodeficiency-associated tumors, such as infusional etoposide, vincristine, and similar to what happens with Burkitt lymphoma doxorubicin with bolus cyclophosphamide and (Dong et al., 2005). prednisone (EPOCH) (Sparano et al., 2010). As PBL is a very aggressive lymphoma, there is a need for Additional anomalies novel therapies such as those targeted against EBV PBL karyotypes are generally complex. An or MYC protein overexpression (Perrine et al., 2007; interesting finding that is noticeable in the Gebauer et al., 2015; Delmore et al., 2011). karyotypes of PBL patients, is that some of the chromosome abnormalities are similar to those Cytogenetics observed in PCM, particularly gain of 1q, loss of 1p, deletions 13q and/or 17p/TP53, and the Cytogenetics morphological simultaneous gain of odd-numbered chromosomes, The most consistent cytogenetic finding in PBL is specifically +3, +5, +7, +9, +11, and/or +15 the presence of a MYC (8q24.2) translocation (Taddesse-Heath et al., 2010). Since similar (Bogusz et al., 2009; Taddesse-Heath et al., 2010; karyotypes can also be observed in some aggressive Valera et al., 2010) typically involving one of the (anaplastic) PCM, it is important to take into immunoglobulins, IGH (14q32.3), IGK (2p11.2), or consideration all available clinical information to IGL (22q11.2). The end result of these differentiate these two entities. translocations is the overexpression of MYC. Interestingly, all of these IG-MYC translocations

Fig.2. 60,XX,del(1)(q25),+2,+3,+5,+7,der(7)t(1;7)(q12;q32)x2,+8,t(8;14)(q24.2;q32.3)x2,+9,add(9)(p22)x2,del(9)(q34),+11, +14,add(15)(p11.2),der(15)(1qter>q12::?::15p11.2>15qter),ins(16;?)(q12.1;?)x2,+17,add(17)(p11.2)x2,+18,+19,add(19)(p13.3),+ 21,add(21)(p11.1),add(21)(p11.2),i(21)(q10),+2mar

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Hsi ED, Lorsbach RB, Fend F, Dogan A. Plasmablastic Genes involved and lymphoma and related disorders. Am J Clin Pathol. 2011 Aug;136(2):183-94 proteins Jambusaria A, Shafer D, Wu H, Al-Saleem T, Perlis C. Cutaneous plasmablastic lymphoma. J Am Acad Dermatol. The translocations involving MYC occur primarily 2008 Apr;58(4):676-8 with the immunoglobulin loci, suggesting that MYC activation plays a crucial role in the development of Luria L, Nguyen J, Zhou J, Jaglal M, Sokol L, Messina JL, Coppola D, Zhang L. Manifestations of gastrointestinal PBL. It has been shown also that the transcription plasmablastic lymphoma: a case series with literature factor PRDM1 (BLIMP1) is highly expressed in review. World J Gastroenterol. 2014 Sep 7;20(33):11894- PBL (Montes-Moreno et al., 2010). One of the 903 functions of this gene is to repress genes that Montes-Moreno S, Gonzalez-Medina AR, Rodriguez-Pinilla maintain mature B-cell identity such as PAX5 and SM, Maestre L, Sanchez-Verde L, Roncador G, Mollejo M, those that are involved in cell proliferation such as García JF, Menarguez J, Montalbán C, Ruiz-Marcellan MC, MYC. Therefore, the frequent incidence of MYC Conde E, Piris MA. Aggressive large B-cell lymphoma with plasma cell differentiation: immunohistochemical translocation in PBL may be an oncogenic characterization of plasmablastic lymphoma and diffuse mechanism that overcomes the repressor effect of large B-cell lymphoma with partial plasmablastic phenotype. BLIMP1. Haematologica. 2010 Aug;95(8):1342-9 Morscio J, Dierickx D, Nijs J, Verhoef G, Bittoun E, References Vanoeteren X, Wlodarska I, Sagaert X, Tousseyn T. Clinicopathologic comparison of plasmablastic lymphoma in Bogusz AM, Seegmiller AC, Garcia R, Shang P, Ashfaq R, HIV-positive, immunocompetent, and posttransplant Chen W. Plasmablastic lymphomas with MYC/IgH patients: single-center series of 25 cases and meta-analysis rearrangement: report of three cases and review of the of 277 reported cases. Am J Surg Pathol. 2014 literature. Am J Clin Pathol. 2009 Oct;132(4):597-605 Jul;38(7):875-86 Castillo J, Pantanowitz L, Dezube BJ. HIV-associated Perrine SP, Hermine O, Small T, Suarez F, O'Reilly R, plasmablastic lymphoma: lessons learned from 112 Boulad F, Fingeroth J, Askin M, Levy A, Mentzer SJ, Di published cases. Am J Hematol. 2008 Oct;83(10):804-9 Nicola M, Gianni AM, Klein C, Horwitz S, Faller DV. A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Castillo JJ, Bibas M, Miranda RN. The biology and Epstein-Barr virus-associated lymphoid malignancies. treatment of plasmablastic lymphoma. Blood. 2015 Apr Blood. 2007 Mar 15;109(6):2571-8 9;125(15):2323-30 Schommers P, Wyen C, Hentrich M, Gillor D, Zoufaly A, Cattaneo C, Facchetti F, Re A, Borlenghi E, Majorana A, Jensen B, Bogner JR, Thoden J, Wasmuth JC, Fätkenheuer Bardellini E, Casari S, Tucci A, Conti G, Rossi G. Oral cavity G, Hoffmann C. Poor outcome of HIV-infected patients with lymphomas in immunocompetent and human plasmablastic lymphoma: results from the German AIDS- immunodeficiency virus infected patients. Leuk Lymphoma. related lymphoma cohort study. AIDS. 2013 Mar 2005 Jan;46(1):77-81 13;27(5):842-5 Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel Sparano JA, Lee JY, Kaplan LD, Levine AM, et al. M, Marafioti T, Schneider U, Huhn D, Schmidt-Westhausen Rituximab plus concurrent infusional EPOCH A, Reichart PA, Gross U, Stein H. Plasmablastic chemotherapy is highly effective in HIV-associated B-cell lymphomas of the oral cavity: a new entity associated with non-Hodgkin lymphoma. Blood. 2010 Apr 15;115(15):3008- the human immunodeficiency virus infection. Blood. 1997 16 Feb 15;89(4):1413-20 Taddesse-Heath L, Meloni-Ehrig A, Scheerle J, Kelly JC, Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs Jaffe ES. Plasmablastic lymphoma with MYC translocation: HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, evidence for a common pathway in the generation of Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, plasmablastic features. Mod Pathol. 2010 Jul;23(7):991-9 Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades Valera A, Balagué O, Colomo L, Martínez A, Delabie J, CS. BET bromodomain inhibition as a therapeutic strategy Taddesse-Heath L, Jaffe ES, Campo E. IG/MYC to target c-Myc. Cell. 2011 Sep 16;146(6):904-17 rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. Am J Surg Pathol. 2010 Dong HY, Scadden DT, de Leval L, Tang Z, Isaacson PG, Nov;34(11):1686-94 Harris NL. Plasmablastic lymphoma in HIV-positive patients: an aggressive Epstein-Barr virus-associated Vega F, Chang CC, Medeiros LJ, Udden MM, Cho-Vega JH, extramedullary plasmacytic neoplasm. Am J Surg Pathol. Lau CC, Finch CJ, Vilchez RA, McGregor D, Jorgensen JL. 2005 Dec;29(12):1633-41 Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. Folk GS, Abbondanzo SL, Childers EL, Foss RD. Mod Pathol. 2005 Jun;18(6):806-15 Plasmablastic lymphoma: a clinicopathologic correlation. Ann Diagn Pathol. 2006 Feb;10(1):8-12 This article should be referenced as such: Gebauer N, Gebauer J, Hardel TT, Bernard V, Biersack H, Meloni-Ehrig A, Hertzberg L. Plasmablastic lymphoma Lehnert H, Rades D, Feller AC, Thorns C. Prevalence of (PBL). Atlas Genet Cytogenet Oncol Haematol. 2017; targetable oncogenic mutations and genomic alterations in 21(2):67-70. Epstein-Barr virus-associated diffuse large B-cell lymphoma of the elderly. Leuk Lymphoma. 2015 Apr;56(4):1100-6

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Leukaemia Section Short Communication

Nodular sclerosis classical Hodgkin lymphoma (NScHL) Antonino Carbone, Annunziata Gloghini Department of Pathology Centro di Riferimento Oncologico Aviano (CRO), Istituto Nazionale Tumori, IRCCS, Aviano, Italy; [email protected] (AC); Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; [email protected] (AG)

Published in Atlas Database: June 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/NodulSclerosClassicHodgkinID1565.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68163/06-2016-NodulSclerosClassicHodgkinID1565.pdf DOI: 10.4267/2042/68163

Nodular sclerosis classical Hodgkin disease Abstract Nodular sclerosis Hodgkin disease Over the past 50 years, a relevant progress has been made toward our understanding of classical Hodgkin Clinics and pathology lymphoma pathology and cell biology. Histologic Note classification evolved through different systems to the 2008 World Health Organization classification, Most patients present with limited disease (Ann upgraded in 2016. Arbor stage II disease) and B symptoms. Mediastinal Nodular sclerosis is a subtype of classical Hodgkin involvement occurs in 80% of cases, usually with lymphoma characterized by sclerosis, diagnostic Bulky disease. Splenic and/or lung involvement, as Hodgkin and Reed-Sternberg cells and other tumour well as bone and bone marrow involvement, are less cells displaying a "lacunar" type morphology. The frequent. architectural pattern consists of grouped lacunar Disease cells in lymphoid nodules surrounded by collagen Based on the characteristics of the Hodgkin and bands. Nodular sclerosis classical Hodgkin Reed-Sternberg (HRS) tumour cells (lacunar cells, lymphoma may have a cellular proliferation of multinucleated giant cells, pseudosarcomatous cells) fibroblasts, in addition to the sclerotic component. and of the reactive infiltrate, four histologic subtypes The amount of sclerosis varies markedly from case of classical Hodgkin lymphoma (cHL) have been to case, from ample sclerosis (total sclerosis phase of distinguished: lymphocyte-rich cHL (LRCHL), nodular sclerosis) to a paucity of collagen associated nodular sclerosis (NS) cHL, mixed cellularity (MC) with abundance of lacunar cells (cellular phase of cHL, and lymphocyte depletion (LD) cHL. Most nodular sclerosis). cHL can be classified as NS or MC subtypes. Keywords NS is a subtype of cHL characterized by sclerosis, Nodular sclerosis subtype of Hodgkin Lymphoma; diagnostic HRS cells and other tumour cells Hodgkin Lymphoma; classical Hodgkin lymphoma; displaying a "lacunar" type morphology. The microenvironment; clinics, pathology; genetics. architectural pattern consists of grouped lacunar cells in lymphoid nodules surrounded by collagen Identity bands. NScHL may have a cellular proliferation of fibroblasts, in addition to the sclerotic component. Other names The amount of sclerosis varies markedly from case Nodular sclerosis classical Hodgkin lymphoma to case, from ample sclerosis (total sclerosis phase of Nodular sclerosis Hodgkin lymphoma

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 71 Nodular sclerosis classical Hodgkin lymphoma (NScHL) Carbone A, Gloghini A

NS) to a paucity of collagen associated with express molecules involved in cancer cell growth abundance of lacunar cells (cellular phase of NS). and survival (such as CD30L or CD40L), and in Phenotype/cell stem origin immune escape (programmed death 1 (PD-1). A fraction of infiltrating CD4+ T cells are regulatory T Cell origin (Treg) cells. Treg cells and PD-1+ T cells also Like Hodgkin and Reed-Sternberg (HRS) cells of interact with HRS cells (Aldinucci et al., 2010; Liu other cHL subtypes, the tumour cells of NScHL et al., 2014; Carbone et al., 2015). derive from preapoptotic crippled Germinal Center (GC) B cells. They are derived from GC B cells that Epidemiology have acquired disadvantageous immunoglobulin Classical Hodgkin lymphoma is a distinct neoplastic variable chain gene mutations (Küppers et al., 2012), entity with heterogeneous epidemiological features. have lost the expression of most B-cell genes and It accounts for approximately 10% of all malignant acquired expression of genes that are typical for lymphomas (Stein et al., 2008).Classical HL is the other types of hematopoietic and lymphoid cells most common cancer in patients under 20 years (Greaves and Gribben 2012; Steidl et al. 2012; (adolescents and younger adults). The first peak of Tiacci et al., 2012). incidence can be observed in patients under 35 years Phenotype of age, whereas a second incidence peak can be Phenotypically, tumour cells of NScHL are CD30 observed in the elderly (Hjalgrim et al, 2008; Stein and CD15 positive (Stein et al., 2008), and exhibit et al., 2008). additional expression of the following markers: NScHL accounts for approximately 70% of cHL in - Plasma cell markers (MUM1/IRF4) usually Europe and USA and is more common in resource positive. rich than in resource poor areas. The incidence of - Molecules involved in Ag presentation (MHC class NScHL is similar in males and females and peaks at II, CD40, CD80, CD86) consistently positive. ages 15-34 years. Cellular components of the cHL microenvironment

Figure 1. "cellular phase" of NScHL. (A) In this variant of NScHL the lacunar cells are numerous. Moreover, they differ morphologically. (B) Grouped lacunar cells show CD30 membranous localization. (C) At higher magnification most lacunar cells appear to be separated from the adjacent lymphoid cells by a clear space. (D) Several sheets of CD30+ lacunar cells with combined membranous and Golgian immunostain.

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Nodular sclerosis classical Hodgkin lymphoma (NScHL) Carbone A, Gloghini A

Cytology eosinophils, granulocytes, histiocytes/macrophages, plasma cells, mast cells, and fibroblast-like cells The recognition of NScHL is based on the presence (Aldinucci et al., 2010). The cellular background of HRS cells and lacunar cells, the specific tumour found in the nodules is variable. The nodules may be cells of NScHL. Binucleated and multinucleated with lymphocyte predominance, mixed or with HRS cells with bi- or multinucleation and huge lymphocyte depletion. The cellular composition of nucleoli are pathognomonic for cHL identification. the backgrounds of the nodules parallel those of non The lacunar cells tend to have more lobated nuclei NS subtype of cHL with less prominent nucleoli and a large amount of cytoplasm than HRS cells in other subtypes of cHL. In formalin-fixed tissues the cytoplasm of the lacunar cells shows retraction so that the cells seem to be located in a lacuna. In the so called "syncytial variant", lacunar cells may be grouped, forming cellular islands which may be associated with necrosis. Pathology Involved tissues by NScHL exhibit a nodular growth pattern with tumour nodules surrounded by collagen Figure 2. Schematic representation of NScHL with early bands. Broad bands of fibroblast-poor collagen may sclerosis, classical sclerosis and total sclerosis. be scarce/absent (cellular phase of NS) or surround one nodule (early sclerosis of NS) or several nodules Other features (classical nodular sclerosis). The fibrosing process EBV infection may progress to reach a complete thickening of the EBV is found in HRS cells preferentially in cases of nodules (total sclerosis of NS). MC and LD cHL, and less frequently in NS and Lacunar cells usually resides in an inflammatory cell LRCHL. Notably, EBV is found in HRS cells in microenvironment. In NScHL, like in other cHL nearly all cases of cHL occurring in patients infected subtypes, microenvironmental cell types include T- with HIV (IARC 2012; Younes et al., 2014; Dolcetti and B-reactive lymphocytes, et al., 2016).

Classical Hodgkin lymphoma subtype EBV infection cHL of the general population cHL, nodular sclerosis Usually absent * cHL, mixed cellularity Usually present * Rare types cHL, lymphocyte rich Variably present cHL, lymphocyte depleted Variably present

HIV-associated HL cHL, lymphocyte depleted Present cHL, mixed cellularity Present Less frequent cHL, lymphohistiocyoid Present cHL, nodular sclerosis Present Post-transplant (cHL type PTLD) Similar to other cHL Present Iatrogenic (methotrexate) cHL, mixed cellularity Variably present (usually present) Table 1. Heterogeneity of classical Hodgkin lymphoma according to the morphologic and virologic characteristics. Abbreviations. cHL, classical Hodgkin lymphoma; PTLD, post-transplant lymphoproliferative disorder *Association with EBV is less frequent in ns (10-40%) than in mc cHL (approximately 75% of cases).

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Nodular sclerosis classical Hodgkin lymphoma (NScHL) Carbone A, Gloghini A

Figure 3. Schematic representation of the interaction of a tumour cell and its cell microenvironment: impact on NFkB signalling pathway. DDR1 pathway is likely to be an alternative or additional pathway to CD40 or CD30 signaling in the pathogenesis of Hodgkin lymphoma.

Treatment After binding to collagen, DDR1 phosphorylation triggers the activation of downstream signaling Like in other cHL subtypes, cure rates approaching pathways, including NF-kB (Das et al., 2006). 80% have been achieved in patients undergoing chemo-radiotherapy, qualifying cHL as a chemosensitive disease (Santoro et al., 1987, Cytogenetics Canellos et al., 2014). Cytogenetics morphological Prognosis See the pertinent sections within the CARDS NScHL exhibit a better prognosis than that of other describing the general features of cHL (Küppers, subtypes of cHL. 2011; Carbone and Gloghini, 2016). Genetics References Note Carbone A, Gloghini A.. Classical Hodgkin lymphoma Atlas Genet Cytogenet Oncol Haematol. in press Recurrent genetic alterations have been identified in HRS cells of cHL (including NScHL). These lesions REFERENCE IARC Monograph on the Evaluation of affect members of the NF-kappaB or JAK/STAT Carcinogenic Risk to Humans. Vol. 100. IARC, Lyon, France, 2012.. A Review of Human Carcinogens. Part B: signalling pathways (Küppers and Re, 2007; Biological Agents Hartmann et al., 2008; Steidl et al., 2010; Küppers Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A. 2011; Küppers et al., 2012; Pasqualucci and Dalla The classical Hodgkin's lymphoma microenvironment and Favera, 2014). See also the pertinent section within its role in promoting tumour growth and immune escape J the CARDS describing the general features of cHL Pathol 2010 Jul;221(3):248-63 (Küppers, 2011; Carbone and Gloghini, 2016). Canellos GP, Rosenberg SA, Friedberg JW, Lister TA, Since NScHL microenvironment contains a Devita VT. Treatment of Hodgkin lymphoma: a 50-year collagen-rich ECM, and a large number of perspective J Clin Oncol 2014 Jan 20;32(3):163-8 fibroblasts, defined HL-associated fibroblasts a Carbone A, Gloghini A, Castagna L, Santoro A, Carlo-Stella lymphomagenetic role for discoidin domain C. Primary refractory and early-relapsed Hodgkin's receptor1 (DDR1), a receptor tyrosine kinase (RTK) lymphoma: strategies for therapeutic targeting based on the (Xu et al., 2011; Valiathan et al., 2012), has been tumour microenvironment J Pathol 2015 Sep;237(1):4-13 proposed. Interactions between HRS cells and HL- Das S, Ongusaha PP, Yang YS, Park JM, Aaronson SA, associated fibroblasts produce collagen-rich reticular Lee SW. Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes fibers composed of collagen I, III and IV covered by chemoresistance through nuclear factor-kappaB pathway the ECM. Importantly, collagen IV, which is recognized by DDR1 in turn induces DDR1 up- activation Cancer Res 2006 Aug 15;66(16):8123-30 regulation and activation (Carbone and Gloghini, 2013).

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Dolcetti R, Gloghini A, Caruso A, Carbone A. A Steidl C, Diepstra A, Lee T, Chan FC, Farinha P, Tan K, lymphomagenic role for HIV beyond immune suppression? Telenius A, Barclay L, Shah SP, Connors JM, van den Berg Blood 2016 Mar 17;127(11):1403-9 doi: 10 A, Gascoyne RD. Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates Greaves P, Gribben JG. Lymphoid neoplasia Laser- with treatment outcome in classical Hodgkin lymphoma capturing the essence of Hodgkin lymphoma Blood Blood 2012 Oct 25;120(17):3530-40 Hartmann S, Martin-Subero JI, Gesk S, Hüsken J, Giefing Steidl C, Telenius A, Shah SP, Farinha P, Barclay L, Boyle M, Nagel I, Riemke J, Chott A, Klapper W, Parrens M, M, Connors JM, Horsman DE, Gascoyne RD. Genome-wide Merlio JP, Küppers R, Bräuninger A, Siebert R, Hansmann copy number analysis of Hodgkin Reed-Sternberg cells ML. Detection of genomic imbalances in microdissected identifies recurrent imbalances with correlations to Hodgkin and Reed-Sternberg cells of classical Hodgkin's treatment outcome Blood 2010 Jul 22;116(3):418-27 lymphoma by array-based comparative genomic hybridization Haematologica 2008 Sep;93(9):1318-26 Stein H, Delsol G, Pileri SA,Weiss LM, Poppema S, Jaffe ES.. Classical Hodgkin lymphoma, introduction. Swerdlow Hjalgrim H, Engels EA. Infectious aetiology of Hodgkin and SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele non-Hodgkin lymphomas: a review of the epidemiological H, Vardiman JW (eds.) World Health Organization evidence J Intern Med 2008 Dec;264(6):537-48 Classification of Tumours, Pathology and Genetics of Küppers R, Engert A, Hansmann ML. Hodgkin lymphoma J Tumours of Haematopoietic and Lymphoid Tissues, Lyon: Clin Invest 2012 Oct;122(10):3439-47 IARC Press, 2008: 326-329. Ku?ppers R, Re D.. Nature of Reed-Sternberg and L H Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Cells, and their Molecular Biology in Hodgkin Lymphoma. Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Hodgkin Lymphoma. Hoppe RT, Mauch PM, Armitage JO, Jaffe ES. The 2016 revision of the World Health et al.,(eds). Lippincott Williams & Wilkins, 2007; 74 - 88 Organization classification of lymphoid neoplasms Blood 2016 May 19;127(20):2375-90 Liu Y, Sattarzadeh A, Diepstra A, Visser L, van den Berg A. The microenvironment in classical Hodgkin lymphoma: an Tiacci E, Döring C, Brune V, van Noesel CJ, Klapper W, actively shaped and essential tumor component Semin Mechtersheimer G, Falini B, Küppers R, Hansmann ML. Cancer Biol 2014 Feb;24:15-22 Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Pasqualucci L, Dalla Favera R.. Molecular Biology of Hodgkin lymphoma Blood 2012 Nov 29;120(23):4609-20 Lymphomas. De Vita, Hellman, and Rosenberg's Cancer: Principles Practice of Oncology. 10th ed. De Vita VTJ, Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Lawrence TS, Rosemberg SA, (eds). Wolters Kluwer Discoidin domain receptor tyrosine kinases: new players in Health/Lippincott Williams & Wilkins, 2014; 1511-1525. cancer progression Cancer Metastasis Rev 2012 Jun;31(1- 2):295-321 Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnoni AM, Bonfante V, Musumeci R, Crippa F, Xu H, Raynal N, Stathopoulos S, Myllyharju J, Farndale et al. Long-term results of combined chemotherapy- RW, Leitinger B. Collagen binding specificity of the discoidin radiotherapy approach in Hodgkin's disease: superiority of domain receptors: binding sites on collagens II and III and ABVD plus radiotherapy versus MOPP plus radiotherapy J molecular determinants for collagen IV recognition by DDR1 Clin Oncol 1987 Jan;5(1):27-37 Matrix Biol 2011 Jan;30(1):16-26 Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Younes A, Carbone A, Johnson P, Dabaja B, Ansell S, Hartmann S, Mechtersheimer G, Klapper W, Vater I, Kuruvilla L.. Hodgkin's lymphoma. De Vita VTJ, Lawrrence Giefing M, Gesk S, Stanelle J, Siebert R, Küppers R. TS, Rosemberg SA (eds). De Vita, Hellman, and TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin Rosenberg's Cancer: Principles Practice of Oncology: lymphoma and primary mediastinal B cell lymphoma J Exp Wolters Kluwer Health/Lippincott Williams & Wilkins; 2014. Med 2009 May 11;206(5):981-9 This article should be referenced as such: Steidl C, Connors JM, Gascoyne RD. Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence Carbone A, Gloghini A. Nodular sclerosis classical of the importance of the microenvironment J Clin Oncol Hodgkin lymphoma (NScHL). Atlas Genet Cytogenet 2011 May 10;29(14):1812-26 Oncol Haematol. 2017; 21(2):71-75.

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Cancer Prone Disease Section Short Communication

Mulibrey nanism Maria Piccione, Emanuela Salzano Department of Sciences for Health Promotion and Mother and Child Care G. D'Alessandro, University of Palermo, Palermo, Italy. [email protected]; [email protected] Published in Atlas Database: December 2015 Online updated version : http://AtlasGeneticsOncology.org/Kprones/MulibreyID10125.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68164/12-2015-MulibreyID10125.pdf DOI: 10.4267/2042/68164

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Clinics Mulibrey (MUscle-LIver-BRain-EYe) nanism is a Phenotype and clinics rare autosomal recessive disorder caused by Growth: Short stature with prenatal onset (birth mutations in TRIM37 gene and characterized by length and birth weight 1.5 – 2 SD below mean with growth failure with prenatal onset, dysmorphic relatively macrocephaly - occipitofrontal head features, muscolar hypotonia, veins congestion circumference 0.5 below SD; adult male height 136- secondary to constrinctive pericarditis and yellowish 161 cm; adult female height 126-151 cm) (Karlberg dots in fundi. Patients present cutaneous nevi et al.2006) flammi, anomalies of gonadal function, type 2 Head: diabetes, fibrous dyasplasia of long bones and an - Craniofacial features: triangular face, low nasal increased risk for Wilms' tumor. Life expectancy bridge, high and broad forehead, and scaphocephaly depends mainly on cardiovascular complications. with occipitofrontal bossing Keywords Mulibrey nanism; TRIM37; dwarfism; - Eye findings: Mild hypertelorism, telecanthus, Wilms'tumor. yellowish dots in fundi, decreased retinal pigmentation with dispersion, hypoplasia of choroid, Identity astigmatism, strabismus (Karlberg et al.2004) - Mouth: relatively small tongue, dental crowding, Other names hypodontia of second bicuspid (Myllarniemi et al. Muscle-liver-brain-eye nanism 1978) Pericardial constriction and growth failure Cardiovascular System: Perheentupa syndrome Constrictive pericarditis, globular shaped heart on x- Inheritance ray, congestive heart failure, myocardial fibrosis, 115 patients described all over the world, 85 of elevated venous pressure, prominent veins in the which from Finland where it has been estimated an neck, congestion in the lungs, abnormal fluid incidence rate of 1/37000 (Karberg et al.2004). It is accumulation in the abdomen (ascites), swelling of an autosomal recessive disorder due to homozygous the arms and/or legs (peripheral edema) or compound heterozygous mutations in the (Perheentupa et al.1973; Cumming et al.1976) TRIM37 gene, (605073) even if sporadic cases have Abdomen: hepatomegaly, sporadic description of been reported in several ethnic groups (Jagiello et urinary tract malformations al.2003).

Muscle: muscular hypotonia

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(2) 76 Mulibrey nanism Piccione M, Salzano E

Central Nervous System: no intellectual disability, Karlberg et al. 2009). dysarthria Treatment Voice: high-pitched voice Skin: cutaneous nevi flammei Patients with constrictive pericarditis may be treated Endocrinology: delayed puberty with irregular with surgery with good results, while treatment with menstrual periods, premature ovarian failure, diuretics and digoxin may be prescribed for those incomplete breast development, infertility, insuline affected by progressive heart failure. resistance type2 diabetes,possible hypoplasia of Hormone replacement therapy may be evaluated in different endocrine glands(Haraldsson 1993; children with growth hormone deficiency, delayed Kalberg et al.2004; Karlberg et al.2007). puberty or very irregular menstrual periods, Radiological findings: hypothyroidism, hypoadrenocorticism and abnormal Cerebral: J-shaped sella turcica, absent or small gonadal function. frontal sinus, absent or small sphenoidal sinus All females should be monitored closely for ovarian Skeletal: slender long bones with thick cortex and tumors, especially in presence of premature ovarian narrow medullary channel, fibrous dysplasia failure (Hamalainen et al., 2006; Karlberg et al. especially in the middle third of tibia. 2006; Karlberg et al. 2009). Evolution Differential Diagnosis Growth failure usually progresses during early Mulibrey nanism shares some clinical aspects infancy; after 10 years of age blood fasting glucose mainly with two other syndromes (Silver Russel levels tend to increase; the diagnosis of Wilms’ Syndrome and 3-M syndrome spectrum (OMIM tumour is usually close to 1 year of age, while after 273750)) characterized by growth failure and puberty all female should undergo to a dysmorphic features (Akawi et al.2011). gynaecological follow-up; GH replacement therapy Neoplastic risk seems to have better short term effects than on the final adult stature (Kalberg et al.2004; Kalberg et Benign tumors especially cystic and benign al.2007). adenomatous lesions have been identified in different organs (renal cortical cysts, pancreatic Prognosis cysts, thyroid lesions); the 22% of patients develop The most life threatening complication is fibrous dysplasia of long bones; 6% of reported represented by cardiac involvement; life expectancy patients were diagnosed for a Wilms tumor. Female also depends strictly on precocious diagnosis of patients with premature ovarian failure are at high respiratory and feeding complications and risk for ovarian fibrothecomas or other stromal malignancies (Balg et al.1995; Lapunzina et al.1995; ovarian cells tumors (Hamalainen et al., 2006; Karlberg et al. 2006).

Three major signs with one minor sign or two major signs with three minor signs are required for the clinical diagnosis. SDS = standard deviation scores. Adapted by Karlberg et al. 2004.

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Comparison between Mulibrey Nanism, Silver-Russell and 3-M Syndromes phenotype.

Cytogenetics Protein Description Note This pleiotropic gene contains 4488 nucleotides The 250 Kb critical cytogenetic region for Mulibrey from 24 exons. The encoded protein is a peroxisomal nanism encompasses the TRIM37 gene locus on member of the tripartite motif (TRIM) family chromosome 17q22 (Avela et al.1997). including a zinc-binding domains, a RING finger Cytogenetics of cancer region, a B-box motif and a coiled-coil domain. TRIM37 is related to some Polycomb group (PcG) A certain number of breast cancer cell lines show multiprotein PRC2-like complex and amplification of the 17q22-23 chromosome region, monoubiquitinates histone H2A, mediating an resulting in an overexpression of TRIM37 gene epigenetic transcriptional repression of target genes( which acts as a promotor of cellular transformation Bhatnagar et al 2014). by silencing onco-suppressor genes . Expression Genes involved and The results of tissue-specific expression levels of both transcripts TRIM37a and TRIM37b measured proteins in multiple tissue cDNA panels by qPCR also show that TRIM37a is ubiquitously expressed with higher TRIM37 (tripartite motif-containing levels in testis and brain, whereas TRIM37b is 37) mainly expressed in testis. In addition tissue level Location 17q22 expression is slightly higher in fetal than in adult DNA/RNA tissue (Hämäläinen et al. 2006). Transcription Mutations Northern blot analysis shows two transcript: the Note first-one, TRIM37a of about 4.5-kb and the second- To date 23 TRIM37 gene mutations have been one, TRIM37b of approximately 3.9 kb. reported as pathogenic variants and 18 of those have

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been associated to mulibrey nanism phenotype. The mutations in an Australian patient with mulibrey nanism. Clin most common Finnish mutation is a 5 bp deletion Genet. 2006 Dec;70(6):473-9 resulting in an aberrant splicing site that causes Haraldsson A, van der Burgt CJ, Weemaes CM, Otten B, frameshift with induction of a stop codon 10 codons Bakkeren JA, Stoelinga GB. Antibody deficiency and isolated growth hormone deficiency in a girl with Mulibrey downstream. Compound heterozygosity for two nanism. Eur J Pediatr. 1993 Jun;152(6):509-12 different mutation has also been found (http://www.ncbi.nlm.nih.gov/clinvar) Jagiello, P., Hammans, C., Wieczorek, S., Arning, L., Stefanski, A., Strehl, H., Epplen, J. T., Gencik, M. A novel splice site mutation in the TRIM37 gene causes mulibrey References nanism in a Turkish family with phenotypic heterogeneity Hum. Mutat. 2003 ; 21: 630-635. Cumming GR, Kerr D, Ferguson CC. Constrictive pericarditis with dwarfism in two siblings (mulibrey nanism). Karlberg N, Karlberg S, Karikoski R, Mikkola S, Lipsanen- J Pediatr. 1976 Apr;88(4 Pt 1):569-72 Nyman M, Jalanko H.. High frequency of tumours in Mulibrey nanism J Pathol. 2009 Jun;218(2):163-71. Akawi NA, Ali BR, Hamamy H, Al-Hadidy A, Al-Gazali L. Is autosomal recessive Silver-Russel syndrome a separate Karlberg, N., Jalanko, H., Perheentupa, J., Lipsanen- entity or is it part of the 3-M syndrome spectrum? Am J Med Nyman, M. Mulibrey nanism: clinical features and diagnostic Genet A. 2011 Jun;155A(6):1236-45 criteria J. Med. Genet. 2004 ; 41: 92-98. Avela K, Lipsanen-Nyman M, Idänheimo N, Seemanová E, Karlberg, S., Tiitinen, A., Lipsanen-Nyman, M. Failure of Rosengren S, Mäkelä TP, Perheentupa J, Chapelle AD, sexual maturation in mulibrey nanism. (Letter) Eng. J. Med. Lehesjoki AE. Gene encoding a new RING-B-box-Coiled- 2004 ; 351: 2559-2560. coil protein is mutated in mulibrey nanism. Nat Genet. 2000 Lapunzina, P., Rodriguez, J. I., de Matteo, E., Gracia, R., Jul;25(3):298-301 Moreno, F.. Mulibrey nanism: three additional patients and Balg S, Stengel-Rutkowski S, Döhlemann C, Boergen K. a review of 39 patients Am. J. Med. Genet. 1995 ; 55: 349- Mulibrey nanism. Clin Dysmorphol. 1995 Jan;4(1):63-9 355. Bhatnagar S, Gazin C, Chamberlain L, Ou J, Zhu X, Tushir Myllarniemi, S., Koski, K., Perheentupa, J. Craniofacial and JS, Virbasius CM, Lin L, Zhu LJ, Wajapeyee N, Green MR. dental study of mulibrey nanism Cleft Palate J. 1978 ;15: TRIM37 is a new histone H2A ubiquitin ligase and breast 369-377. cancer oncoprotein. Nature. 2014 Dec 4;516(7529):116-20 Perheentupa, J., Autio, S., Leisti, S., Raitta, C., Tuuteri, L.. Hämäläinen RH, Joensuu T, Kallijärvi J, Lehesjoki AE. Mulibrey nanism, an autosomal recessive syndrome with Characterisation of the mulibrey nanism-associated pericardial constriction Lancet 1973 ; 302: 351-355. TRIM37 gene: transcription initiation, promoter region and alternative splicing. Gene. 2006 Jan 17;366(1):180-8 This article should be referenced as such: Hämäläinen RH, Mowat D, Gabbett MT, O'brien TA, Piccione M, Salzano E. Mulibrey nanism. Atlas Genet Kallijärvi J, Lehesjoki AE. Wilms' tumor and novel TRIM37 Cytogenet Oncol Haematol. 2017; 21(2):76-79.

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