VolumeVolume 23 1 -- NumberNumber 91 MaySeptember - September 2019 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

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

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

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

Editorial correspondance

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

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

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

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

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

Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Department of Health Sciences, University of Milan, Italy; [email protected] Beghini Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 François Desangles Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, Kessel The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research Oskar A. Haas Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 23, Number 9, September 2019

Table of contents

Gene Section

AARD (alanine and arginine rich domain containing protein) 253 Jean Loup Huret GLS (Glutaminase) 256 José A. Campos-Sandoval, Mercedes Martin-Rufián, Javier Márquez TNFRSF9 (TNF receptor superfamily member 9) 269 Anette Gjörloff Wingren, Barnabas Nyesiga

Leukaemia Section t(1;1)(q24;q25) RCSD1/ABL2 inv(1)(q24q25) RCSD1/ABL2 274 Baptiste Gaillard -20 or monosomy 20 277 Adriana Zamecnikova Ocular adnexal marginal zone lymphoma (OAMZL) 281 Lucia Bongiovanni, Maurilio Ponzoni t(1;5)(q21;q32) PDE4DIP/PDGFRB t(1;5)(q21-23;q32) TPM3/PDGFRB t(1;5)(q21-23;q31-33) 288 Adriana Zamecnikova t(4;12)(q21;p13) 293 Tatiana Gindina t(20;21)(q11;q22) RUNX1/NOL4L 295 Jean-Loup Huret

Solid Tumour Section

Kidney: Succinate dehydrogenase-deficient renal cell carcinoma 297 Paola Dal Cin

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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AARD (alanine and arginine rich domain containing protein) Jean Loup Huret [email protected] (JLH)

Published in Atlas Database: January 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/AARDID60018ch8q24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70526/01-2019-AARDID60018ch8q24.pdf DOI: 10.4267/2042/70526 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract the mouse Aard promoter (see below). Review on AARD, with data on DNA, on the Transcription protein encoded, and where the gene is implicated. Transcript (hg38), including UTRs: Keywords chr8:116,938,199-116,944,487, size: 6,289bp on AARD; Transcription factor; Signal transduction strand +; coding region: chr8:116,938,244- mediator; Developmental protein 116,942,701, size: 4,458bp, according to UCSC. AARD has 2 splice variants, one of these 2 Identity transcripts codes for a protein. Transcript length: 2299 bp, coding sequence: 468 Other names: C8orf85 nt. 2 exons; exon 1 codes for aa 1-109, exon 2 HGNC (Hugo): AARD codes for aa 110-155 (Vega). Location: 8q24.11 Local Order: Protein RAD21 chr8:116,846,905-116,852,252 Description RAD21-AS1 chr8:116,874,424-116,876,868 155 amino acids (aa), 17575Da. MIR3610 chr8:116,874,728-116,874,800 Of note are an Ala/Arg-rich domain of 46 aa in aa AARD 60-105, with a long stretch of alanine in aa 82-88, SLC30A8 chr8:117,135,259-117,176,714 four leucine zippers at aa 56-63 (LEDLRRRL), 101-108 (LARLRAEL), 118-125 (LARTLLDL), DNA/RNA 125-132 (LNMKVQQL), and 3 phosphorylation sites (serine/threonine kinases) in aa 95-98 Description (TGVE), 121-124 (TLLD) and 146-149 (SPKD). A potential androgen response element (ARE) The rat Aard (named rA5D3) 165 aa long is sequence (1637 to 1632, TGTTCT) was found in sequenced and described in Blomberg et al., 2002.

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 253 AARD (alanine and arginine rich domain containing protein) Huret JL

Figure 1. AARD gene and protein

2005; Beverdam and Koopman, 2006). Strong testis-specific expression was also detected in the adult mouse (Svingen et al., 2007). It is also expressed in adult liver, kidney, brain, lung, muscle, heart and bladder of mice (Geng et al., 2017). AR (androgen receptor) mediates the effects of androgens by binding to the androgen response Figure 2. ModBase predicted comparative 3D structure elements (ARE) of target genes. (Pieper et al., 2014 An ARE (TGTTCT) was identified at position - Expression 1637 to -1632 in the promoter region near the mouse Aard transcription initiation site. AARD is expressed prenatally in male gonads, and AR binds this ARE and activates Aard in most organs postnatally (see below). transcription. Localisation Aard is directly regulated by AR in Sertoli cells of AARD is detected in lipid droplets (The Human mouse testis (Geng et al., 2017). Protein Database). Implicated in Function The presence of leucine-zipper domains and Top note phosphorylation sites suggest that AARD is a AARD RNA is enriched in breast cancer, but the transcription factor, and may be involved in signal gene product is not prognostic (The Human Protein transduction pathways (Blomberg et al., 2002). Database). Aard is upregulated early during postnatal rat lung Lung adenocarcinoma development, but also in the heart, kidney, liver, A t(8;9)(q24;p24) RIC1/AARD has been found in and testis, but the developmental expression lung adenocarcinoma (Yoshihara et al. 2015; Hu et pattern, although comparable in levels of al., 2018). expression, was different -in term of timing- in each of the tissues studied (Blomberg et al., 2002). Aard is one of the 266 or 1083 genes, according to the References different studies, upregulated in gonads of male but Beverdam A, Koopman P. Expression profiling of purified -not in female- mice embryos. This strong mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate expression was restricted to the sex cords (Menke genes for human sexual dysgenesis syndromes. Hum Mol and Page, 2002; Bouma et al., 2004; Nef et al., Genet 2006 Feb 1;15(3):417-31

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 254

AARD (alanine and arginine rich domain containing protein) Huret JL

Blomberg LA, Chan WY, Clerch LB, Massaro D. Molecular Descombes P, Parker KL, Vassalli JD. Gene expression cloning and characterization of a novel gene upregulated during sex determination reveals a robust female genetic early during postnatal rat lung development. Biochim program at the onset of ovarian development. Dev Biol Biophys Acta 2002 Apr 12;1574(3):391-8 2005 Nov 15;287(2):361-77 Bouma GJ, Hart GT, Washburn LL, Recknagel AK, Eicher Pieper U, Webb BM, Dong GQ, Schneidman-Duhovny D, EM. Using real time RT-PCR analysis to determine Fan H, Kim SJ, Khuri N, Spill YG, Weinkam P, Hammel M, multiple gene expression patterns during XX and XY Tainer JA, Nilges M, Sali A. ModBase, a database of mouse fetal gonad development. Gene Expr Patterns 2004 annotated comparative protein structure models and Nov;5(1):141-9 associated resources. Nucleic Acids Res 2014 Jan;42(Database issue):D336-46 Geng Q, Ni LW, Ouyang B, Hu YH, Zhao Y, Guo J. Alanine and arginine rich domain containing protein, Aard, Svingen T, Beverdam A, Verma P, Wilhelm D, Koopman is directly regulated by androgen receptor in mouse Sertoli P. Aard is specifically up-regulated in Sertoli cells during cells. Mol Med Rep 2017 Jan;15(1):352-358 mouse testis differentiation. Int J Dev Biol 2007;51(3):255- 8 Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K, Lang FM, Martinez-Ledesma E, Lee SH, Zheng S, Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Verhaak RGW. TumorFusions: an integrative resource for Vegesna R, Kim H, Verhaak RG. The landscape and cancer-associated transcript fusions. Nucleic Acids Res therapeutic relevance of cancer-associated transcript 2018 Jan 4;46(D1):D1144-D1149 fusions. Oncogene 2015 Sep 10;34(37):4845-54

Menke DB, Page DC. Sexually dimorphic gene expression This article should be referenced as such: in the developing mouse gonad. Gene Expr Patterns 2002 Dec;2(3-4):359-67 Huret JL. AARD (alanine and arginine rich domain containing protein). Atlas Genet Cytogenet Oncol Nef S, Schaad O, Stallings NR, Cederroth CR, Pitetti JL, Haematol. 2019; 23(9):253-255. Schaer G, Malki S, Dubois-Dauphin M, Boizet-Bonhoure B,

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 255 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

GLS (Glutaminase) José A. Campos-Sandoval, Mercedes Martin-Rufián, Javier Márquez Department of Molecular Biology and Biochemistry, Faculty of Sciences, Campus de Teatinos, University of Málaga, 29071 Málaga, Spain, and Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; [email protected], [email protected], [email protected]

Published in Atlas Database: February 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/GLSID45600ch2q32.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70527/02-2019-GLSID45600ch2q32.pdf DOI: 10.4267/2042/70527 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

towards the development of small-molecule Abstract inhibitors of GLS. After metabolic reprogramming, many cancer cells Keywords become glutamine addicted, that is, they depend on Glutaminase, glutamine addiction, anticancer a high consumption of this amino acid for their therapy, BPTES, CB-839, compound 968, breast survival and proliferation. Glutaminase catalyzes cancer, colorectal cancer, glioblastoma, the stoichiometric conversion of L-glutamine to L- hepatocellular carcinoma, leukemia, lung cancer, glutamate and ammonium ions, the first step of melanoma, ovarian cancer, prostate cancer. glutaminolysis. GLS gene encodes two isoforms, known as kidney-type glutaminase (KGA) and glutaminase C (GAC). Upregulation of GLS is a Identity common feature of many tumors and, in recent Other names: GA; KGA; GAC; PAG years, this enzyme and its interacting partners have attracted much attention as potential new targets for HGNC (Hugo): GLS (Glutaminase) cancer therapy. Considerable effort is being devoted Location: 2q32.2

Figure 1. Genomic structure of human glutaminase GLS gene and alternative transcripts KGA and GAC. Introns are depicted as solid light blue lines and exons as numbered dark blue boxes. Dashed red or dotted black lines indicate the exons involved in the generation of KGA and GAC transcripts, respectively (Campos-Sandoval et al., 2015).

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 256 GLS (Glutaminase) Campos-Sandoval JA et al.

The MTOR complex 1/ RPS6KB1 DNA/RNA (mTORC1/S6K1 (mammalian target of rapamycin complex 1/ribosomal protein S6 kinase beta-1)) Description signaling pathway positively regulates GLS Human GLS gene is located on chromosome 2 expression by enhancing the translation efficiency (Aledo et al., 2000). It is composed of 19 exons and of Myc mRNA. spans approximately 82 kb (Porter et al., 2002). The After inhibition of mTORC1 with rapamycin, an gene resides on the forward strand. It starts at increase in miR-23a/b levels was observed (Csibi et 190880821 and ends at 190965552 from pter al., 2014). (NCBI, GeneID 2744). The activation of RELA (v-rel avian Transcription reticuloendotheliosis viral oncogene homolog A, also known as p65), a member of nuclear factor Two different transcripts coding for functional kappa B (NF-kB) family, also decreases miR-23a proteins arise from this gene by a mechanism of expression in leukemic cells, inducing GLS alternative splicing: a long KGA transcript, first expression (Rathore et al., 2012). isolated from brain, which contains exons 1-14 and Another transcription factor, JUN (v-jun avian 16-19 of the GLS gene (Nagase et al., 1998; sarcoma virus 17 oncogene homolog), when Holcomb et al., 2000; Porter et al., 2002), and a activated downstream of oncogenic Rho GTPase shorter GAC transcript, formed by the first 15 signaling, increases GLS expression in breast exons and originally described in human colon cancer cells by direct binding to its gene promoter cancer cells (Elgadi et al., 1999). A third transcript (Lukey et al., 2016). After being activated by has been found in heart and skeletal muscle that transforming growth factor (TGF)-β and Wnt codes for a much shorter protein (GAM) with no (Wingless-type MMTV integration site family)-3a, measurable catalytic activity (Elgadi et al., 1999). the homeodomain transcription factor DLX2 Several mechanisms regulate glutaminase (distal-less homeobox-2), involved in embryonic expression. The first one to be described is based on and tumor development, also upregulates GLS the presence of AU-rich pH-responsive instability expression (Lee SY et al., 2016a). elements within the 3'-nontranslated region of GLS Transcription of GLS gene is also activated in HIV- mRNA. These elements are implicated in the rapid 1 infected cells by interferon (IFN)-α through signal turnover of mRNAs by exonucleolytic degradation. transducer and activator of transcription 1 (STAT1) The onset of metabolic acidosis results in the phosphorylation, leading to glutamate increased binding activity of a RNA-binding overproduction (Zhao et al., 2012). protein CRYZ (identified as ζ-crystallin/NADPH Retinoblastoma protein (RB1), a tumor suppressor quinone reductase) with high affinity for the pH- that modulates cell cycle checkpoints, also regulates responsive elements, that selectively stabilizes GLS glutamine metabolism. mRNA (Hansen et al., 1996; Tang and Curthoys, Deletion of RB family revealed an increase in GLS 2001). Upregulation of GAC by the long non- protein and activity (Reynolds et al., 2014). coding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) has recently been reported in Protein colon cancer. This lncRNA interacts with the cleavage factor I (CFIm) complex in an allele- Note specific manner and select the poly(A) site within In recent years, considerable effort is being devoted 14th intron of GLS pre-mRNA, resulting in the towards the development of small-molecule preferential splicing of GAC isoform (Redis et al., inhibitors that target GLS and its interacting 2016). MicroRNAs (miRNAs) are also implicated partners (Katt et al., 2017; Matés et al., 2018). in GLS expression. Through downregulation of Structural information of truncated or full MIR23A / MIR23B, which target GLS mRNA, the recombinant human GLS complexed with substrate oncogenic transcription factor MYC (v?myc (glutamine), product (glutamate), the allosteric myelocytomatosis viral oncogene homolog) activator phosphate or inhibitors is now available indirectly relieves repression of GLS in lymphoma (DelaBarre et al., 2011; Cassago et al., 2012; and prostate cancer cells (Gao et al., 2009). Thangavelu et al., 2012; Pasquali et al., 2017).

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Figure 2. Schematic diagram of GLS isoforms showing the localization of predicted domains and motifs by sequence analysis (Márquez et al., 2016).

Description APC/C-Cdh1 (anaphase-promoting complex/cyclosome-Cdh1) which targets KGA for Purification: degradation by the proteasome (Colombo et al., A 10000-fold purification of glutaminase (KGA) 2011). The GLS precursor also has a putative N- from pig kidney was achieved by Kvamme et al. terminal mitochondrial targeting sequence of 16 (1970) using alternative solubilization and residues (Shapiro et al., 1991). The Curthoys precipitacion steps, based on its property to laboratory, in a series of studies on the biosynthesis aggregate in phosphate-borate buffers and to and processing of the rat KGA, found that the 74 disaggregate in Tris-HCl buffers. KGA may appear kDa precursor is processed in the mitochondria by a as three different forms: a dimeric and inactive matrix processing peptidase to yield two subunits of form in Tris-HCl buffer; a tetrameric and active 66 (cleavage site at residue 72) and 68 kDa with a form after combination of two dimers when 3:1 stoichiometry (Perera et al., 1990; Srinivasan et dialyzed against phosphate buffer; and a polymeric al., 1995). For the human GLS, only a 66 kDa form with mass higher that 2000 kDa in the protein has been detected when expressed as a presence of phosphate-borate buffer. These recombinant protein using the baculovirus polymers consist of double-stranded helices expression system (Holcomb et al., 2000). As (Kvamme at al., 1970; Olsen et al., 1970; Godfrey previously described for GLS2 (Olalla et al., 2002), et al., 1977). GLS proteins show a LXXLL motif or nuclear Structure: receptor box from Leu144 to Leu148 (Cassago et KGA transcript (ORF: 2010 nt) codes a 669- al., 2012). In recent years, several groups have residues protein, with a predicted molecular mass of revealed the structure of GLS based on X-ray 73.5 kDa. GAC transcript (ORF: 1797 nt) codes a crystallography. In the asymmetric unit, GLS is 598-residues protein, with a predicted molecular organized as a tetramer where the monomers mass of 65.5 kDa. Both precursors are identical in interact through two sets of interfaces at the almost all their primary structure (exons 1-14, glutaminase domains. This domain is composed of residues 1-550), except in the C-terminal region two subdomains: an α/β subdomain that contains (residues 551-669 for KGA; 551-598 for GAC). five-stranded anti-parallel β-sheet surrounded by They are composed of a N-terminal domain folded several α-helices, and an α-helical subdomain with into an EF-hand-like four-helix bundle (Pasquali et seven α-helices. Two GLS monomers are joined by al., 2017) and a central glutaminase domain from a long interface of their respective α-helical residues 220 to 530, which belongs to the beta subdomains to form an inactive dimer. Two lactamase/transpeptidase-like superfamily and opposing dimers then associate by a short interface contains the catalytic active site (Thangavelu et al., involving two pairs of equivalent anti-parallel α- 2012). In addition, the C-terminal region of KGA helices (α-13) at the α /β subdomains, which come possesses three ankyrin repeats, also present in into contact by hydrophobic interactions. GLS2 proteins but not in the GAC isoform (DeLaBarre et al., 2011; Cassago et al., 2012; (Pasquali et al., 2017), and KEN (Lys-Glu-Asn) and Thangavelu et al, 2012). When a phenylalanine D (destruction) boxes. The ankyrin repeats are residue (Phe394 in the mouse GAC) in the short protein-protein interaction modules of 33 residues dimer interface was mutated to a serine one, GAC that have been found in many important proteins persisted as an inactive dimer even at high such as transcriptional factors, cell cycle regulators, concentrations of phosphate (Cassago et al., 2012). cytoskeletal organizers, etc. (Sedgwick and The presence of salt bridges between Asp391 and Smerdon, 1999; Mosavi et al., 2004). Both KEN Lys401 at both ends of the pairing helices further and D boxes are recognized by the ubiquitin ligase

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stabilizes the quaternary structure. The replacement Cayman ataxia and dystonia. This protein interacts of Asp391 by a lysine residue had a similar effect to with KGA through a conserved protein-protein that caused by the phenylalanine substitution (Li et interaction domain known as the BNIP-2 and al., 2016). Cdc42GAP homology (BCH) domain. Caytaxin Kinetic properties: regulates the intracellular localization and activity Both GLS isoforms require a polyvalent anion to be of KGA: it relocalized KGA from cell body to active. A decade after Krebs (1935) proposed the neurite terminals and reduced glutamate levels by existence of two different types of glutaminase, one inhibiting its activity (Buschdorf et al., 2006). of them (GLS) strongly inhibited by the product Subsequently, another member of the family of glutamic acid, Carter and Greenstein (1947) BCH-domain containing proteins, PRUNE2 (prune observed an accelerated deamidation of glutamine homolog 2 with BCH domain, also known as in aqueous rat-liver extracts in the presence of BMCC1s), has been shown to directly interact with phosphate, arsenate or sulfate and suggested that KGA. This protein, associated to microtubules and this effect could be due to an augmentation of the intermediate filaments in astrocytes and neurons, activity of glutaminase enzyme. Errera and may influence import of KGA to mitochondria: Greenstein (1949) characterized it as phosphate- overexpression of PRUNE2 in mouse neurons led activated glutaminase. It was later found that to an accumulation of KGA within the cytoplasm phosphate induced the association of catalytically (Boulay et al., 2013). Very recently, GLS has been inactive dimers into active tetramers, whereas reported to interact with peroxisome proliferator- glutamate caused inhibition of glutaminase by activated receptor gamma ( PPARG) in the nuclei reversing this process (Godfrey et al., 1977; of prostate cancer cells, and this interaction Morehouse and Curthoys, 1981). At a concentration decreased the nuclear receptor activity (de Guzzi of phosphate of 100 mM, tetramerization of Cassago et al., 2018). glutaminase is produced and the enzyme reaches its Post-translational modifications: maximum activity. The activation by phosphate is Aside from the regulation of GLS gene expression, sigmoidal, with a K0.5 of 25 mM and a Hill index of several post-translational modifications affect 1.5. When phosphate concentration is increased, glutaminase activity, with implications for cancer both the inhibition by glutamate -which is cells metabolism. Most of the identified competitive with respect to glutamine- and the KM modifications correspond to phosphorylation of for glutamine decrease (Haser et al., 1985). serine, tyrosine and threonine residues (see Although the activity of the purified enzyme is Ascenção et al., 2018 for references), although the completely dependent on added phosphate, it was effect of specific modified residues on GLS activity not known if the high concentration of phosphate has only recently been studied. Thangavelu et al. required for the in vitro reaction could also occur in (2012) revealed that GLS activity in human breast the intracellular site of glutaminase action or adenocarcinoma cells was dependent on whether phosphate was the substitute of an phosphorylation by epidermal growth factor (EGF) unknown natural activator (Sayre and Roberts, via the RAF/MEK/ERK signaling module and was 1958). In addition to phosphate, a wide variety of completely abolished after treatment with MEK physiological compounds (tricarboxylic acids, inhibitors or co-expression with protein nucleotide triphosphates, acyl-CoA derivatives) phosphatase PP2A. Han et al. (2018) have recently was found that could act as activators (or inhibitors) found that GLS activity is drastically reduced when of glutaminase (O'Donovan and Lotspeich, 1966; one of the ten identified phosphorylation sites, Weil-Malherbe, 1969; Kvamme and Torgner, Ser314 at the glutaminase domain, is mutated to 1975). However, recent X-ray analysis has provided alanine. A remarkable reduction in Ser314 support for the candidature of phosphate as a phosphorilation and GLS activity occurs when cell relevant in vivo effector: crystal structure of lysates of several tumor types are treated with glutaminase shows that each GAC monomer alkaline phosphatase. This phosphorylation is encloses a single phosphate ion inside its active regulated by the NF-kB-PKCε (PRKCE protein site. It has been proposed that, after binding of kinase C-epsilon) axis. After treatment with a NF- phosphate, a flexible activation loop located near kB inhibitor, GLS activity could be restored with the short dimer interface undergoes a major the overexpression of PKCε (Han et al., 2018). In conformational change that stabilizes the active site contrast, phosphorylation of Ser95 at the N- and promotes catalytic turnover (Thangavelu et al., terminal domain inhibits GLS activity, but its 2012; Li et al., 2016, Stalnecker et al., 2017). mechanism of deregulation in cancer cells is still Interacting partners: unknown (Ascenção et al., 2018). Another post- The first binding partner for KGA to be described translational modification that affects GLS activity was the caytaxin ATCAY (or BNIP-H for BNIP-2 is succinylation. The mitochondrial protein sirtuin 5 homology), a protein exclusively expressed in (SIRT5), which removes short-chain acyl moieties neural tissues and encoded by a gene linked to from lysine residues, regulates GLS activity by

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reducing its level of succinylation (Polleta et al., Curthoys and Watford, 1995). In human tissues, the 2015). Acetylation has also been speculated to KGA isoform is expressed in kidney, brain, heart, regulate GLS activity. Several lysine residues that lung and pancreas, but not in skeletal muscle or occur at the α-helix-13 has been identified as sites liver (Aledo et al., 2000). The human GAC isoform, of this modification and their acetylation could first described in a cancer cell line, is found prevent the formation of active tetramers principally in cardiac muscle and pancreas, at lower (McDonald et al., 2015). As already mentioned levels in lung, kidney and placenta, and is not above, KGA is also modified by ubiquitination at detected in brain or liver. (Elgadi et al., 1999). GLS its C-terminal region (Colombo et al., 2011). proteins are also overexpressed in a wide variety of Drug inhibitors: tumors compared to normal tissues, with GAC The first glutaminase inhibitors to be discovered being the predominant isoform in many of them, several decades ago were L-glutamine analogs such as breast carcinoma (Elgadi et al., 1999), isolated from Streptomyces, such as azaserine, prostate cancer (Gao et al., 2009), non-small cell diazo-O-norleucine (DON) and acivicin. They act lung cancer (van den Heuvel et al., 2012), leukemia as irreversible competitive inhibitors for GLS and (Pérez-Gómez et al., 2005; Matre et al., 2016), other glutamine-utilizing enzymes: DON binds glioma (Szeliga et al., 2008; Tanaka et al., 2015), covalently to residue Ser286 at the GLS active site among others. (Thangavelu et al., 2014). Although they show a Localisation significant inhibitory effect on several types of tumors in preclinical tests, their pronounced Errera and Greenstein (1949) proposed for the first toxicity has compromised the therapeutical time a mitochondrial location for glutaminase in potential of these compounds (Ahluwalia et al., liver, and subsequently different authors 1990). The bisthiadiazole derivatives form the demonstrated experimentally this location in both second important group of inhibitors that was liver and other organs such as kidney, brain and described the past few years, the prototype being intestine (Klingman and Handler, 1958; Guha, BPTES (Robinson et al., 2007). A more potent 1961; Katunuma et al., 1967; Pinkus and derivative of BPTES, CB-839 (Gross et al., 2014), Windmueller, 1977). However, some authors have is being tested in clinical trials (more information at described a non-mitochondrial cytoplasmic pool of http://www.clinicaltrials.gov database). These non- glutaminase (Aoki et al., 1991). In a recent study competitive allosteric inhibitors bind to the with several tumor cell lines, Cassago et al. (2012) interface between two dimers, stabilizing an have reported a cytosolic localization for KGA, inactive tetrameric form of GLS (DeLaBarre et al., with only GAC located in mitochondria. These 2011; Thangavelu et al., 2012). The newest findings suggest that the intracellular localization of molecule in this group is the compound GLS may depend on other factors other than the UPGL00004, with similar binding affinity as CB- mitochondrial targeting sequence at its N-terminus. 839 but with better microsomal stability (Huang et The sub-mitochondrial location of glutaminase has al., 2018). The third group of inhibitors is been studied extensively, but it is still a represented by compound 968, a controversial issue. Although glutaminase seems to benzophenanthridinone that binds to a pocket at the be associated with the inner mitochondrial interface between two GLS monomers. Unlike membrane (IMM), different orientations of the BPTES, compound 968 preferentially binds to the enzyme have been proposed: to both sides of the monomeric, inactive form of GLS, and is unable to IMM (Kvamme and Olsen, 1979), the inhibit GLS which has been pre-activated with intermembrane space (c-side) (Kvamme et al., phosphate (Wang et al., 2010; Stalnecker et al., 1991; Roberg et al., 1995), or the matrix space (m- 2017). Other new GLS inhibitors recently described side) (Shapiro et al., 1985; Aledo et al., 1997). are physapubescin K, (Cheng et al., 2017; Wu et al., Function 2017), zaprinast (Elhammali et al., 2014) and brachyantheraoside A8 (Li et al., 2017). One GLS (E.C. 3.5.1.2.) catalyzes the hydrolytic essential point of GLS inhibition is that these novel deamidation of L-glutamine to form L-glutamate compounds lack the high degree of toxicity and ammonium, the first step of glutaminolysis. observed with glutamine mimetics (Matés et al., This enzyme fulfills essential tasks related to tissue- 2018). For an overview of glutaminase inhibitors, specific function. In kidney, glutaminase reaction is see: Katt et al., 2017; Song et al., 2018; Wu et al., the initial step in renal ammoniagenesis. As 2018; Xu et al, 2018. mentioned above, GLS is induced through its mRNA stabilization in response to metabolic Expression acidosis. This results in an increased consumption The rat KGA isoform has been found in all of glutamine extracted from plasma in the proximal nonhepatic tissues with glutaminase activity, convolute tubules and the excretion of the generated including fetal liver (Smith and Watford, 1990; ammonium ions in the urine. The further

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metabolization of α-ketoglutarate (α-KG) yields elevated expression of GAC but not KGA (Gross et bicarbonate ions that are transported into blood to al., 2014). The new GLS inhibitor UPGL00004 had restore the acid-base balance (Curthoys, 2001). In a similar effect: it potently inhibited growth in brain, GLS participates in the synthesis and TNBC but not in receptor-positive cells (Huang et recycling of glutamate, the principal excitatory al., 2018). A higher activity of MYC in cells of this neurotransmitter, through the astrocytic-neuronal subtype could maintain expression of GLS (Kung et glutamate-glutamine cycle (Nicklas et al., 1987; al., 2011). Another effect of GLS inhibition with Daikhin and Yudkoff, 2000). Knockout mice for CB-839 was a decrease in MTOR activity. Both the Gls gene die shortly after birth due to impaired GLS and mTOR inhibition synergized in TNBC glutamatergic synaptic function, stressing the cells (Lampa et al., 2017). GLS expression is also importance of this enzyme in glutamatergic upregulated by ERBB2 activation. When non- transmission (Masson et al., 2006). Moreover, it has tumorigenic breast epithelial cells were transformed been shown that small interfering RNA (siRNA) with a constitutive active form of ERBB2, GLS silencing of GLS in neural progenitor cells mRNA and protein levels were increased through impaired their differentiation, proliferation and activation of NF-kB signaling (Qie et al., 2014). In survival, suggesting a critical role of GLS in a similar model, knockdown of ephrin-A1, a ligand neurogenesis (Wang et al., 2014). of EPH receptor A2 ( EPHA2), enhanced GLS Besides its role in normal tissues, glutaminase is activity through increased levels of Rho GTPase highly expressed in tumors, where its activity has and addition of α-KG restored proliferation been correlated with malignancy (Knox et al., 1967; inhibited by compound 968 (Youngblood et al., Linder-Horowitz et al., 1969; Kovacevik and 2016). Activation of JUN downstream of Rho McGivan, 1983). Many cancer cells develop what GTPase signaling led to enhanced glutaminase has been called "glutamine addiction", a term now activity (Lukey et al., 2016). An inverse correlation widely used to reflect the strong dependence for between the expression of glutamine synthetase this essential nitrogen substrate after metabolic (GS, encoded by GLUL) and GLS has been reprogramming (Wise et al., 2008). Silencing GLS observed in luminal and TNBC cells. Moreover, expression by genetic knockdown or inhibiting its GLUL repression led to an increase of GLS mRNA activity with drug inhibitors reveal the critical role levels, and ectopic GDH over-expression reduced of GLS in this addiction. Thus, the specific those levels (Kung et al., 2011). inhibition of GLS by antisense mRNA slowed Colorectal cancer tumor cell growth and induced phenotypic changes that made these cells vulnerable to the host's GLS expression is upregulated in colorectal cancer immune system (Lobo et al., 2000; Segura et al., (CRC) tissues compared to adjacent normal tissues 2001). In addition, GLS enables cancer cells to (Huang et al., 2014). In recent years, several counteract ROS. Glutamate is the precursor of mechanisms have been described to regulate GLS glutathione (GSH) and a source or reducing expression in colorectal cancer. Supranutritional equivalents (Hensley et al., 2013). Based on the doses of selenite induced GLS ubiquitination by abundant published data on recent years on the role APC/C-CDH1, leading to suppression of of glutaminase in cancer, this enzyme has become a glutaminolysis and increasing apoptosis in CRC potential drug target for therapeutic intervention cells (Zhao et al., 2017). Heat shock factor 1 ( (Matés et al., 2018). HSF1) participates in malignant transformation in many types of tumors. In CRC, high levels of HSF1 Implicated in correlates with poor survival. Through inhibition of MIR137 which targets GLS, HSF1 stimulates GLS Breast cancer expression, resulting in enhanced glutaminolysis Breast cancer exhibits subtype-specific phenotype and MTOR activation (Li et al., 2018). MYCN of glutamine dependence. Triple negative breast downstream regulated gene 2 ( NDRG2), a tumor cancer (TNBC) showed higher GLS expression suppressor, has been shown to regulate GLS than ERBB2 (Erb-B2 receptor tyrosine kinase 2)- expression. When overexpressed in CRC cells, positive or luminal subtypes (Kung et al., 2011; NDRG2 inhibited glucolysis and glutaminolysis via Kim et al., 2013; Lampa et al., 2017). In a study repression of MYC. (Xu et al., 2015). GLS with a panel of breast cancer cell lines, GLS expression seems to be also regulated by TP53. inhibitor CB-839 had an anti-proliferative effect on Costunolide, a natural sesquiterpene lactone with TNBC cells but not on estrogen receptor (ER)- antitumoral activity, stimulated the nuclear positive or ERBB2-positive cell lines. This effect translocation of TP53 and downregulated GLS was associated with a significant decrease in both mRNA and protein levels, resulting in lower glutamine consumption and levels of tricarboxylic intracellular levels of glutamate and α-KG. acid (TCA) cycle intermediates. Sensitivity of Treatment with a TP53 inhibitor rescued GLS TNBC cells to CB-839 was correlated with an expression, indicating that activation of TP53 was

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required for costunolide to downregulate GLS study, a large set of clinical samples of HCC and expression in CRC cells (Hu et al., 2018). normal liver was analysed and GLS was found to be highly expressed in tumor samples, whereas Glioblastoma GLS2 was preferentially expressed in normal cells. The effect of glutaminase inhibition on During malignant progression, a switch from GLS2 glioblastoma (GBM) have been addressed in to GLS was observed. High GLS and/or low GLS2 isocitrate dehydrogenase ( IDH1 or IDH2) wild expression in HCC determined poor prognosis in type or mutant cell lines. GBM cells that harbour patients with this tumor (Yu et al., 2015). Several IDH mutations acumulate 2-hydroxyglutarate (2- mechanisms that regulate GLS expression in HCC HG), an oncometabolite primarily derived from have been described. Wnt/β-catenin pathway, glutamine (Dang et al., 2009). When compared to associated to HCC stemness, promotes GLS IDH wild type cells, IDH mutant cells treated with expression. After treatment with an agonist of the GLS inhibitor BPTES showed a slower growth Wnt/β-catenin pathway, both GLS mRNA and rate that could be restored by adding exogenous α- protein increased. In addition, the increase in ROS KG (Seltzer et al., 2010). 2-HG inhibits the caused by treatment with compound 968 decreased synthesis of glutamate by α-KG-dependent the amount of nuclear β-catenin ( CTNNB1) and branched-chain amino acid aminotransferases subsequently inhibited expression of target genes BCAT1 and BCAT2 and, as a consequence, implicated in HCC stemness (Li et al., 2019). dependence of these cells on glutaminase for RELA also controls GLS expression in HCC and its glutamate and GSH biosynthesis increases. inactivation reduced GLS mRNA levels. Inhibition of GLS with CB-839 made IDH mutant Dysregulation of RELA and GLS correlated with cells more susceptible to reactive oxygen species poor prognosis in HCC patients (Dong et al., 2018). (ROS)-induced cell death and radiation. Based on HCC cells with a mesenchymal phenotype showed these findings, a combination of CB-839, the higher levels of TGF-β than their epithelial alkylating agent temozolomide and radiation is now counterparts, and this resulted in increased GLS being tested in patients with IDH1 mutant gliomas expression and glutamine anaplerosis (Soukupova (McBrayer et al., 2018). ROS generation by et al., 2017). A lncRNA that participates in HCC treatment with oxidizing agents synergized with progression, HOXA distal transcript antisense RNA GLS silencing or GLS2 overexpression to suppress ( HOTTIP), is negatively regulated by MIR192 and malignant properties of GBM cells (Martèn-Rufián MIR204 and this regulation modulates GLS et al., 2014). In IDH wild type GBM cells, expression. Inhibition of HOTTIP by siRNA or by pharmacological NOTCH pathway blockade ectopic expression of miR-192/-204 suppressed reduced the levels of GLS mRNA, which was GLS expression and hence HCC proliferation (Ge reflected in reduced intracellular glutamate et al., 2015). A therapeutic strategy combining GLS concentration (Kahlert et al., 2016). MiRNAs also inhibition with ROS induction has been tested in play an important role in glutamine metabolism of HCC cells. Treatment with compound 968 and glioblastoma. Thus, MIR153 has been found to be dihydroartemisinin (an anti-cancer drug that downregulated in glioblastoma and its enhances ROS production) synergistically overexpression inhibits cell growth and promotes sensitized HCC cells to ROS-induced cytotoxicity apoptosis by directly targeting GLS expression (Liu resulting in apoptosis (Wang et al., 2016). et al., 2017). Compensatory anaplerotic mechanisms have also been described in GBM. In Leukemia those that use glutamine as the preferred anaplerotic In a study with leukemia cells from medullar blood precursor, inhibition of GLS is accompanied by of human patients, both GLS and GLS2 isoforms augmented activity of pyruvate carboxylase to were expressed, although GLS accounted for the stimulate glycolytic metabolism (Cheng et al., majority of glutaminase activity in these cells. 2011). Conversely, glioblastoma cells respond to Furthermore, GLS expression was positively deficit in glycolysis after mTOR inhibition by correlated with the rate of proliferation (Pérez- increasing glutamine metabolism through elevated Gómez et al., 2005). Acute myeloid leukemia GLS expression. Combination of MTOR and GLS (AML) cells that harbour IDH mutations are inhibition caused suppression of tumor growth in glutamine addicted and their growth could be vivo (Tanaka et al., 2015). suppressed by treatment with BPTES (Emadi et al., 2014). Analysis of AML cell lines showed high Hepatocellular carcinoma levels of GAC, while KGA was expressed at low Hepatocellular carcinoma (HCC) is one of the most level. Inhibition of GLS with BPTES or CB-839 aggressive cancers. A high correlation between caused reduction of key metabolites downstream of growth rate and dedifferentiation of rat hepatomas glutamate, including TCA cycle intermediates and and GLS activity was already described 50 years GSH. CB-839 exposure also reduced levels of ago (Linder-Horowitz et al., 1969). In a recent oncometabolite 2-HG and this reduction associated

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with signs of differentiation (Matre et al., 2016). lung cancer cells, targeted inhibition of EGFR Combined therapy with GLS inhibitors signaling and GLS with erlotinib and CB-839, dramatically reduced proliferation in AML models. respectively, induced a reduction in glucose and Thus, GAC inhibition by CB-839 sinergized with glutamine transporters levels and led to tumor BCL2 (B-Cell Leukemia/Lymphoma 2) (Jacque et regression in xenograft models (Momcilovic et al., al., 2015) or FLT3 (FMS-like tyrosine kinase 3) 2017). Unfortunately, acquired resistance is inhibition (Gregory et al., 2018) to induce loss of developed by patients with NSCLC after several viability through apoptotic cell death. Synergistic months of treatment with erlotinib. Compound 968, antileukemic effects were also observed after when combined with erlotinib, inhibited the treatment with BPTES in combination with proliferation of erlotinib-resistant NSCLC cells by NOTCH1 inhibition (Herranz et al., 2015). decreasing the expression of EGFR (Xie et al., MiRNAs have also been implicated in glutamine 2016). The adquired resistance of lung squamous metabolism in leukemic cells. Thus, an increase in cell carcinomas to MTOR inhibition via enhanced expression and translocation of RELA to the glutaminolysis was overcome by treatment with nucleus was observed in leukemic Jurkat T cells CB-839 (Momcilovic et al., 2018). growing in medium with glutamine, which caused a Melanoma higher NF-kB activity. Activation of RELA reduced MIR23A expression, leading to a higher Two miRNAs targeting GLS have been found to be expression of GLS. Overexpression of MIR23A in downregulated in melanoma cells and their low these cells impaired glutamine metabolism and levels associated with poor prognosis. When caused mitochondrial dysfunction and cell death overexpressed, both miRNAs (MIR137 and (Rathore et al., 2012). MIR203) suppressed glutamine catabolism and proliferation of melanoma cells (Chang et al., 2016; Lung cancer Luan et al., 2018). MiRNA203 also sensitized GAC is the predominant GLS isoform in resistant melanoma cells to temozolomide (Chang glutamine-dependent non-small cell lung cancer et al., 2016). (NSCLC). The increased GAC:KGA ratio observed in these cells, compared with normal lung tissue, Ovarian cancer was due to a significant decrease of KGA Patients with ovarian cancer who initially respond expression in tumoral cells. GAC knockdown in to platinum and taxane-based chemotherapy will glutamine-dependent cells strongly reduced cell develop drug resistance. Compared to sensitive growth, whereas the effect of KGA knockdown was cells, cisplatin-resistant cells showed glutamine much less pronounced, suggesting that GAC is the dependence, associated with the upregulated more essential GLS isoform in these cells (van den expression of glutamine transporter SLC1A5 Heuvel et al., 2012). GAC protein levels were (ASCT2) and GLS mediated by higher levels of similar between tumor and normal tissues: the high MYC. GLS overexpression in cisplatin-sensitive glutaminase activity in NSCLC cells resulted from cells resulted in increased resistance to this agent. GAC phosphorylation (Han et al., 2018). However, Conversely, knockdown of GLS re-sensitized other authors have found that GLS expression is resistant cells to cisplatin. Combination of BPTES significantly higher in NSCLC than in cells from and cisplatin synergistically increased apoptosis normal lung tissues (Lee JS et al., 2016b). A 2-fold (Hudson et al., 2016). A similar effect on cell increase in GAC levels and a reduction in KGA and proliferation was obtained after treatment of pyruvate carboxylase levels were observed in ovarian cancer cells with paclitaxel and compound NSCLC cells that underwent ephitelial to 968. This GLS inhibitor induced cell cycle arrest mesenchymal transition induced by TGF-β, making and apoptosis, and sensitized cells to paclitaxel these cells more susceptible to GLS inhibition, as (Yuan et al, 2016). Moreover, knockdown of both shown by impaired TCA cycle anaplerosis and GLS isoforms by siRNA sensitized cells to increased sensitivity to oxidative stress after chemotherapy more effectively than depletion of treatment with BPTES (Ulanet et al., 2014). GAC or KGA alone (Masamha and LaFontaine, Synergic treatments that combine inhibition of GLS 2018). Another proposed therapeutic strategy and other drug targets have been described in recent combined inhibition of PI3K/Akt/mTOR axis studies. Thus, treatment with GLS inhibitor (frequently activated in ovarian cancer cells) and compound 968 sensitized lung cancer cells to GLS with PP242 (an inhibitor of mTORC1 and apigenin-mediated apoptosis (Lee YM et al., mTORC2) and CB-839, respectively. GLS 2016c). Dual treatment with GLS inhibitor BPTES inhibition resulted in a dramatic induction of and thymidylate synthase inhibitor 5-fluorouracil PP242-mediated cell death not only by a reduced resulted in the reversal of NSCLC in a preclinical glutamine anaplerosis, but also by a decreased level xenograft model (Lee JS et al., 2016b). In of phosphorylated STAT3 (signal transducer and epidermal growth factor receptor ( EGFR) mutant activator of transcription 3) (Guo et al., 2016).

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Gene Section Review

TNFRSF9 (TNF receptor superfamily member 9) Anette Gjörloff Wingren, Barnabas Nyesiga Biomedical science, Health and society, Malmö University, Malmö, Sweden [email protected]; [email protected]

Published in Atlas Database: January 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/TNFRSF9ID42631ch1p36.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70528/01-2019-TNFRSF9ID42631ch1p36.pdf DOI: 10.4267/2042/70528 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

chromosome 1p36, a region that also harbors genes Abstract of several other members of this receptor family Review on TNFRSF9 (CD137), with data on DNA, (e.g., TNFRSF1B (TNFR2), TNFRSF8 (CD30), on the protein encoded, and where the gene is TNFRSF4 (OX40) and TNFRSF25 (Apo3)) and is implicated. associated with deletions and rearrangements in Keywords several malignancies including neuroblastomas, myelodysplastic syndrome, and refractory acute TNFRSF9; CD137; tumor necrosis factor receptors; non-lymphocytic leukemia (Schwarz 1997). Immune response; T cell response. Human CD137 gene Human CD137 consists of 255 amino acids with Identity two potential N-linked glycosylation sites Other names: CDw137, CD137, ILA (Alderson 1994). Hydrophobicity analysis revealed HGNC (Hugo): TNFRSF9 amino acids 1-17 to be a putative signal peptide Location: 1p36.23 followed by an extracellular domain of 169 amino acids and then a transmembrane domain of 27 DNA/RNA amino acids between positions 187-213 and lastly a short intracellular domain of 42 amino acids Description (Alderson 1994). The molecular weight of the CD137 is a member of the tumor necrosis factor protein was calculated to be 27 kDa (Zhou 1995) receptor superfamily 9 (TNFRSF9) first identified and was shown to be 60% identical to murine in mice (Kwon 1989, Kwon 1994) and found to CD137 (Alderson 1994). Five regions of amino map to murine chromosome 4 at the 75.5 cM acid sequences were conserved between mice and position. Schwarz et al. isolated a 1.4-kb full-length human in the cytoplasmic domain an indication that cDNA from a library constructed from activated these residues might be important for CD137 human T-cell leukemia virus (HTLV) type 1- function (Alderson 1994). Murine and human transformed human T-lymphocytes (Schwarz CD137 ligands were identified and cloned by 1993). Schwarz et al. localized the CD137 gene to Alderson et al.(Alderson 1994).

Figure 1. Mapping of CD137 gene on chromosome1p36 (from GeneCards CD137 gene).

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 269 TNFRSF9 (TNF receptor superfamily member 9) Gjörloff Wingren A, Nyesiga B

The human TNFSF9 (CD137L) consisted of 254 containing potential phosphorylation sites (Schwarz amino acids and its gene maps to chromosome 19 1993). in the region 19p13.3 (Alderson 1994). The human Structure: Bitra et al.determined the crystal CD137-L shows 36% amino acid identity with its structure of mCD137 to 2.2 Å resolution and found murine counterpart (Alderson 1994). High-affinity that similar to other TNFRSFs, mCD137 has four binding of huCD137 Fc to either native or cysteine rich domains (CRDs). However, the recombinant human CD137-L was also organization of CRD1 and the orientation of CRD3 demonstrated (Alderson 1994). The murine CD137 and CRD4 with respect to CRD2 in the mCD137 ligand consists of 309 amino acid polypeptide and structure distinctly differed from those of other its gene maps to murine chromosome 17 (Goodwin TNFRSFs (Bitra 2017). 1993). Expression Mouse CD137 gene The CD137 gene in mice spans approximately 13kb In humans, CD137 expression has been reported in and consists of 10 exons, two of them in the 50 follicular DCs (Lindstedt 2003), monocytes untranslated regions and eight in the coding region (Kienzle 2000), hepatoma cells (Schwarz 1995) and (Kwon 1994). Nucleotide sequence analysis of blood vessels from individuals with malignant CD137 showed a single open reading frame, which tumors (Broll 2001). Expression of CD137 soluble codes for a polypeptide 256 amino acids in length form has been reported in the serum of patients with a calculated molecular mass of 27.5kDa with rheumatoid arthritis (Michel 1998). Incresed (Kwon 1994). The first 23 amino acids were shown expression of CD137 in human peripheral blood to be a signal peptide, followed by a cysteine-rich mononuclear cells post exposure to mitomycin and region, which comprised of four potential TNFR other DNA damaging agents, such as doxorubicin, motifs, of which the first was partial and the third bleomycin and girradiation (Kim 2002). Expression distinct from those of the TNFR (Kwon 1994). of CD137L was observed following stimulation of Almost 30% of the amino acids residing between professional antigen presenting cells (APCs) residues 140-185, a part that follows the ligand including dendritic cells (DCs) and macrophages as binding domain, were serine or threonines. These well as activated B cells in both human and mice provide a potential site for O-linked glycosylation (Alderson 1994, Goodwin 1993, Pollok 1994, while amino acids 186-211 form the hydrophobic Futagawa 2002, DeBenedette 1997). CD137 is also transmembrane domain which is followed by the expressed by follicular DC, monocytes, mast cells, stop-transfer sequence containing several basic granulocytes, and endothelial cells (Anderson residues (Kwon 1994).The carboxyl terminal part 2012). Anderson et al. described CD137 protein of the cytoplasmic domain contains two short runs expression by follicular DC in the germinal center of three and four acidic residues, respectively, and a and scattered paracortical T cells, but not by normal sequence of five glycines followed by a tyrosine germinal-center B cells, bone marrow progenitor (Kwon 1994). cells, or maturing thymocytes. CD137 expression was also observed on activated natural killer (NK) Transcription (Malero 1998), dendritic cells (DC)(Futagawa CD137 was found to be induced on CD4+ and 2002) as well as neutrophils (Heinisch 2000 ) in CD8+ T cells in mice and humans (Kwon 1989, mice. Schwarz 1995, Vinay 1998, Pollok 1993). In mice, Localisation the expression takes several hours after stimulation, increases slowly, culminates at 60 hours and Using immunohistochemical studies on human declines again by 110 hours (Goodwin 1993, Vinay tissue samples to determine in vivo CD137 1998, Pollok1994). In humans, CD137 mRNA was expression in non-immune tissue samples, Broll et detected 1.5 hours after stimulation on T al. found a strong CD137 expression in blood lymphocytes, reaching maximal levels at 8 hours, vessel walls, on the endothelial layer, and on the and declining to background levels by 48 hours vascular smooth muscle cells. (Schwarz 1995). Function The CD137L-CD137 pathway is known to co- Protein stimulate T cells to carry out effector functions such as eradication of established tumors (Melero 1997, Description Ye 2002) as well as the broadening of primary and CD137 is a 30-kDa glycoprotein and exists as both memory CD8+ T cell responses (Halstead 2002, a monomer and a 55-kDa dimer on the T cell Bertram 2002). Signals moderated by CD137 have surface (Kwon 1994).The CD137 gene encodes a been shown to induce a novel subpopulation of 255-amino acid protein with 3 cysteine-rich motifs CD11c+ CD8+ T cells that have strong anti-cancer in the extracellular domain, a transmembrane and anti-autoimmune effects (Vinay 2006). A novel region, and a short N-terminal cytoplasmic portion carbohydrate-mediated interaction between CD137

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and LGALS9 (Galectin-9 (Gal-9)) was identified inflammation, excessive mucus production, and and it was demonstrated in several immune elevated IgE during a 7 week observation period. responses that Gal-9 plays a significant role in They further established that the disease is CD137 signaling activities (Madireddi 2014). Gal-9 completely reversed by anti-CD137 mAb binds to terminal galactose moieties of N-linked administration (Polte 2006). glycans within the CRD4 region of CD137 and Human atherosclerosis there is no competition between this binding with the binding of CD137 to its natural ligand CD137L CD137 is expressed in human atherosclerosis and or to agonist antibodies against CD137 (Bitra its activation promotes inflammation and disease 2017). Bitra et al. also demonstrated that Gal-9 development in murine atherosclerosis (Söderström facilitates signaling and functional activation of 2014). Söderström et al. showed that the minor T CD137 in mouse T cells, DCs and NK cells upon allele of rs2453021 is associated with increased binding mouse CD137L or agonist antibodies to intima-media thickness in the common carotid CD137 (Bitra 2017). Once ligated and crosslinked, artery and increased risk of incident non-cardiac CD137 interacts with the tumor necrosis factor vascular events, thus providing the first human (TNF)-associated factors 1 and 2 ( TRAF1 and genetic evidence for involvement of CD137 in TRAF2), a process that leads to activation of the atherosclerosis (Söderström 2014). master immuno-regulatory transcription factor NF- Crystalline silica-induced lung κB (Chester 2016). In T cells, CD137 signaling inflammation and fibrosis results into upregulation of the anti-apoptotic B-cell lymphoma-extra large ( BCL2L1 (Bcl-xl)), B-cell Li et al. found that CD137 is induced in response to lymphoma 2 ( BCL2) pathways and induces crystalline silica injury in lungs and that it is highly proliferation and production of pro-inflammatory expressed during development of experimental cytokines interferon gamma ( IFNG (IFN-γ)) and silicosis. The CD137 pathway signaling was IL2 (Lee 2002, Snell 2011). Additionally, CD137 discovered to enhance inflammatory response and stimulation causes an increase in signaling through promote pulmonary fibrosis induced by crystalline the T-cell receptor (TCR) and amplifies the silica (Li 2016). cytotoxicity of CD8+ T cells (Shuford 1997). Colorectal cancer Similarly, in NK cells, CD137 stimulation enhances Dimberg et al. investigated whether CD137 and proliferation, IFN-γ production, and cytolytic action CD137L protein levels are altered in colorectal (Melero 1998). In DCs, CD137 ligation speeds up tumours compared with paired normal tissues. They maturation through upregulation of B7 co- examined CD137 and CD137L plasma levels from stimulatory molecules ( CD80 and CD86) and patients with colorectal cancer. Collectively, they elevates survival and production of IL6 and IL12 observed a significant lower CD137L level in (Kuang 2012). Anti-CD137 immunotherapy has cancerous tissue compared with paired normal recently shown promise as a treatment for solid tissue and the difference in CD137L protein level tumors and lymphoid malignancies in preclinical was significantly lower in the colon cancer models (Anderson 2012). The mode of action subgroup compared with paired normal colon underlying CD137-mediated tumor regression tissue. In addition, an elevated CD137 protein level consists of multiple, complimentary antitumor in the rectal cancer subgroup compared with paired immune pathways. Mainly, CD137 agonism normal rectal tissue was observed. Higher soluble activates a potent, cytotoxic T-cell population that CD137 protein concentration was detected in the can infiltrate and lyse tumors (Curran 2013). In plasma of patients with a tumour localised in the addition to direct tumor lysis, CD137 stimulation colon compared to those with a tumour localised in stimulates secretion of type 1 cytokines, creating an the rectum. A tendency of higher CD137L protein inflammatory, immunogenic cytokine milieu within concentration in the plasma from patients with the tumor microenvironment (Li 2003). Finally, colon tumour localization was observed. They also CD137 ligation increases the secretion of perforin ( observed a strong correlation between plasma PRF1), granzyme and activation of the Fas ligand ( concentrations of CD137 and CD137L proteins. FASLG) effector system by both CD8+ T cells and Their work revealed how different expression levels NK cells (Morales-Kastresana 2013). of CD137 and CD137L in the colon and rectum may indicate that various mechanisms are involved Implicated in in the pathogenesis of colorectal cancer and lead to Asthma dissimilar protective immunity (Dimberg 2006). Polte et al. used a murine asthma model to Crohn's disease demonstrate how a single injection of an anti- Maerten et al. investigated whether CD137 (CD137) mAb prevents the development of CD137/CD137L interactions might be involved in airway hyper reactivity, eosinophilic airway the pathogenesis of Crohn's disease (CD) and found

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that CD137 expression on lamina propria LP cells influenza infection. J Immunol. 2002 Apr 15;168(8):3777- in inflamed and to a lesser extend in non-inflamed 85 gut tissue from CD patients. They also found Bitra A, Doukov T, Wang J, Picarda G, Benedict CA, Croft elevated CD137 mRNA levels in intestinal CD M, Zajonc DM. Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4- tissue. Their results suggest that CD137/CD137L 1BB signaling. J Biol Chem. 2018 Jan 26;293(4):1317- interactions contribute to the persistence of gut 1329 inflammation in CD (Maerten 2004). Broll K, Richter G, Pauly S, Hofstaedter F, Schwarz H. Type 1 diabetes CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am J Clin Pathol. 2001 Forsberg et al. reported suppression of type 1 Apr;115(4):543-9 diabetes (T1D) progression in NOD mice by Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding CD137 deficiency. From their findings, blockage the accelerator to cancer immunotherapy Cancer Immunol of the CD137-CD137 ligand interaction Immunother 2016 Oct;65(10):1243-8 significantly delayed T1D onset in NOD mice and Cheuk AT, Mufti GJ, Guinn BA. Role of 4-1BB:4-1BB absence of CD137 or its interaction with CD137 ligand in cancer immunotherapy Cancer Gene Ther 2004 ligand led to suppression of T1D progression. They Mar;11(3):215-26 also demonstrated that soluble CD137 produced by Choi BK, Kim YH, Lee DG, Oh HS, Kim KH, Park SH, Lee regulatory T cells contributed to their autoimmune- J, Vinay DS, Kwon BS. In vivo 4-1BB deficiency in suppressive function in this model. Their results myeloid cells enhances peripheral T cell proliferation by suggest that CD137 can either promote or suppress increasing IL-15 J Immunol 2015 Feb 15;194(4):1580-90 T1D development in NOD mice depending on Curran MA, Geiger TL, Montalvo W, Kim M, Reiner SL, Al- where it is expressed (Forsberg 2017). Shamkhani A, Sun JC, Allison JP. Systemic 4-1BB activation induces a novel T cell phenotype driven by high Hodgkin lymphoma expression of Eomesodermin J Exp Med 2013 Apr 8;210(4):743-55 Anderson et al. showed that CD137 protein is expressed by a selected group of hematolymphoid DeBenedette MA, Shahinian A, Mak TW, Watts TH. Costimulation of CD28- T lymphocytes by 4-1BB ligand J tumors, including classical Hodgkin lymphoma, T- Immunol 1997 Jan 15;158(2):551-9 cell and NK/T-cell lymphomas, and follicular Dimberg J, Hugander A, Wågsäter D. Expression of dendritic cells neoplasms (Anderson 2012). CD137 and CD137 ligand in colorectal cancer patients Malignant and benign tumors Oncol Rep 2006 May;15(5):1197-200 Forsberg MH, Ciecko AE, Bednar KJ, Itoh A, Kachapati K, In the 32 healthy tissue samples they examined, Ridgway WM, Chen YG. CD137 Plays Both Pathogenic none contained CD137-positive vessels while and Protective Roles in Type 1 Diabetes Development in malignant tumors had a significantly enhanced NOD Mice J Immunol 2017 May 15;198(10):3857-3868 frequency of CD137-expressing blood vessels Futagawa T, Akiba H, Kodama T, Takeda K, Hosoda Y, (11/34). In benign tumors (2/14) and in Yagita H, Okumura K. Expression and function of 4-1BB inflammatory tissues (2/9) only a minority had and 4-1BB ligand on murine dendritic cells Int Immunol CD137-expressing vessels (Broll 2001). Salih et al. 2002 Mar;14(3):275-86 described CD137 expression on various human Goodwin RG, Din WS, Davis-Smith T et al. Molecular carcinoma cell lines, on cells of solid tumors cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology derived from these cell lines, and cells obtained to tumor necrosis factor Eur J Immunol 1993 from human tumors (Salih 2000). Oct;23(10):2631-41 Halstead ES, Mueller YM, Altman JD, Katsikis PD. In vivo References stimulation of CD137 broadens primary antiviral CD8+ T cell responses Nat Immunol 2002 Jun;3(6):536-41 Alderson MR, Smith CA, Tough TW, Davis-Smith T, Armitage RJ, Falk B, Roux E, Baker E, Sutherland GR, Din Heinisch IV, Daigle I, Knöpfli B, Simon HU. CD137 WS. Molecular and biological characterization of human 4- activation abrogates granulocyte-macrophage colony- 1BB and its ligand. Eur J Immunol. 1994 Sep;24(9):2219- stimulating factor-mediated anti-apoptosis in neutrophils 27 Eur J Immunol 2000 Dec;30(12):3441-6 Anderson MW, Zhao S, Freud AG, et al. CD137 is Kienzle G, von Kempis J. CD137 (ILA/4-1BB), expressed expressed in follicular dendritic cell tumors and in classical by primary human monocytes, induces monocyte Hodgkin and T-cell lymphomas: diagnostic and therapeutic activation and apoptosis of B lymphocytes Int Immunol implications. Am J Pathol. 2012 Sep;181(3):795-803 2000 Jan;12(1):73-82 Bansal-Pakala P, Croft M. Defective T cell priming Kim KM, Kim HW, Kim JO, Baek KM, Kim JG, Kang CY. associated with aging can be rescued by signaling through Induction of 4-1BB (CD137) expression by DNA damaging 4-1BB (CD137). J Immunol. 2002 Nov 1;169(9):5005-9 agents in human T lymphocytes Immunology 2002 Dec;107(4):472-9 Bertram EM, Lau P, Watts TH. Temporal segregation of 4- 1BB versus CD28-mediated costimulation: 4-1BB ligand Kuang Y, Weng X, Liu X, Zhu H, Chen Z, Chen H. Effects of 4-1BB signaling on the biological function of murine influences T cell numbers late in the primary response and dendritic cells Oncol Lett 2012 Feb;3(2):477-481 regulates the size of the T cell memory response following

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Kwon BS, Kozak CA, Kim KK, Pickard RT. Genomic Polte T, Foell J, Werner C, Hoymann HG, Braun A, organization and chromosomal localization of the T-cell Burdach S, Mittler RS, Hansen G. CD137-mediated antigen 4-1BB J Immunol 1994 Mar 1;152(5):2256-62 immunotherapy for allergic asthma J Clin Invest 2006 Apr;116(4):1025-36 Kwon BS, Weissman SM. cDNA sequences of two inducible T-cell genes Proc Natl Acad Sci U S A 1989 Qi Y, Zhao R, Cao H, Sui X, Krantz SB, Zhao ZJ. Mar;86(6):1963-7 Purification and characterization of protein tyrosine phosphatase PTP-MEG2 J Cell Biochem 2002;86(1):79- Lee HW, Park SJ, Choi BK, Kim HH, Nam KO, Kwon BS. 89 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1 J Immunol 2002 Söderström LÅ, Gertow K, Folkersen L, Sabater-Lleal M, Nov 1;169(9):4882-8 et al. Human genetic evidence for involvement of CD137 in atherosclerosis Mol Med 2014 Oct 14;20:456-65 Li C, Du S, Lu Y, Lu X, Liu F, Chen Y, Weng D, Chen J. Blocking the 4-1BB Pathway Ameliorates Crystalline Silica- Salih HR, Kosowski SG, Haluska VF, Starling GC, Loo DT, induced Lung Inflammation and Fibrosis in Mice Lee F, Aruffo AA, Trail PA, Kiener PA. Constitutive Theranostics 2016 Sep 9;6(12):2052-2067 expression of functional 4-1BB (CD137) ligand on carcinoma cells J Immunol 2000 Sep 1;165(5):2903-10 Li Q, Carr A, Ito F, Teitz-Tennenbaum S, Chang AE. Polarization effects of 4-1BB during CD28 costimulation in Sanchez-Paulete AR, Labiano S, Rodriguez-Ruiz ME, generating tumor-reactive T cells for cancer Azpilikueta A, Etxeberria I, Bolaños E, Lang V, Rodriguez immunotherapy Cancer Res 2003 May 15;63(10):2546-52 M, Aznar MA, Jure-Kunkel M, Melero I. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for Lindstedt M, Johansson-Lindbom B, Borrebaeck CA. translation into successful cancer immunotherapy Eur J Expression of CD137 (4-1BB) on human follicular dendritic Immunol 2016 Mar;46(3):513-22 cells Scand J Immunol 2003 Apr;57(4):305-10 Schwarz H, Arden K, Lotz M. CD137, a member of the Madireddi S, Eun SY, Lee SW, Nemcovicová I, Mehta AK, tumor necrosis factor receptor family, is located on Zajonc DM, Nishi N, Niki T, Hirashima M, Croft M. chromosome 1p36, in a cluster of related genes, and Galectin-9 controls the therapeutic activity of 4-1BB- colocalizes with several malignancies Biochem Biophys targeting antibodies J Exp Med 2014 Jun 30;211(7):1433- Res Commun 1997 Jun 27;235(3):699-703 48 Schwarz H, Tuckwell J, Lotz M. A receptor induced by Maerten P, Geboes K, De Hertogh G, Shen C, Cadot P, lymphocyte activation (ILA): a new member of the human Bullens DM, Van Assche G, Penninckx F, Rutgeerts P, nerve-growth-factor/tumor-necrosis-factor receptor family Ceuppens JL. Functional expression of 4-1BB (CD137) in Gene 1993 Dec 8;134(2):295-8 the inflammatory tissue in Crohn's disease Clin Immunol 2004 Sep;112(3):239-46 Shuford WW, Klussman K, Tritchler DD, et al. 4-1BB costimulatory signals preferentially induce CD8+ T cell Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L. proliferation and lead to the amplification in vivo of NK1 1 cells express 4-1BB (CDw137) costimulatory cytotoxic T cell responses J Exp Med 1997 Jul molecule and are required for tumor immunity elicited by 7;186(1):47-55 anti-4-1BB monoclonal antibodies Cell Immunol Snell LM, Lin GH, McPherson AJ, Moraes TJ, Watts TH. T- Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, cell intrinsic effects of GITR and 4-1BB during viral Hellström KE, Mittler RS, Chen L. Monoclonal antibodies infection and cancer immunotherapy Immunol Rev 2011 against the 4-1BB T-cell activation molecule eradicate Nov;244(1):197-217 established tumors Nat Med 1997 Jun;3(6):682-5 Vinay DS, Cha K, Kwon BS. Dual immunoregulatory Michel J, Langstein J, Hofstädter F, Schwarz H. A soluble pathways of 4-1BB signaling J Mol Med (Berl) 2006 form of CD137 (ILA/4-1BB), a member of the TNF receptor Sep;84(9):726-36 family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis Eur Vinay DS, Kwon BS. Role of 4-1BB in immune responses J Immunol 1998 Jan;28(1):290-5 Semin Immunol 1998 Dec;10(6):481-9 Morales-Kastresana A, Catalán E, Hervás-Stubbs S, et al. Won EY, Cha K, Byun JS, Kim DU, Shin S, Ahn B, Kim Essential complicity of perforin-granzyme and FAS-L YH, Rice AJ, Walz T, Kwon BS, Cho HS. The structure of mechanisms to achieve tumor rejection following treatment the trimer of human 4-1BB ligand is unique among with anti-CD137 mAb J Immunother Cancer 2013 May members of the tumor necrosis factor superfamily J Biol 29;1:3 Chem 2010 Mar 19;285(12):9202-10 Oh HS, Choi BK, Kim YH, Lee DG, Hwang S, Lee MJ, Ye Z, Hellström I, Hayden-Ledbetter M, Dahlin A, Park SH, Bae YS, Kwon BS. 4-1BB Signaling Enhances Ledbetter JA, Hellström KE. Gene therapy for cancer using Primary and Secondary Population Expansion of CD8+ T single-chain Fv fragments specific for 4-1BB Nat Med Cells by Maximizing Autocrine IL-2/IL-2 Receptor Signaling 2002 Apr;8(4):343-8 PLoS One 2015 May 11;10(5):e0126765 Zhou Z, Kim S, Hurtado J, Lee ZH, Kim KK, Pollok KE, Palma C, Binaschi M, Bigioni M, Maggi CA, Goso C. Kwon BS. Characterization of human homologue of 4-1BB CD137 and CD137 ligand constitutively coexpressed on and its ligand Immunol Lett 1995 Feb;45(1-2):67-73 human T and B leukemia cells signal proliferation and This article should be referenced as such: survival Int J Cancer 2004 Jan 20;108(3):390-8 Gjörloff Wingren A, Nyesiga B. TNFRSF9 (TNF receptor Pollok KE, Kim YJ, Hurtado J, Zhou Z, Kim KK, Kwon BS. superfamily member 9). Atlas Genet Cytogenet Oncol 4-1BB T-cell antigen binds to mature B cells and Haematol. 2019; 23(9):269-273. macrophages, and costimulates anti-mu-primed splenic B cells Eur J Immunol 1994 Feb;24(2):367-74

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Leukaemia Section Short Communication t(1;1)(q24;q25) RCSD1/ABL2, inv(1)(q24q25) RCSD1/ABL2 Baptiste Gaillard Laboratoire d'Hématologie CHU Reims, France; [email protected]

Published in Atlas Database: October 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/inv1q24q25RCSD1ABL2ID1831.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70529/10-2018-inv1q24q25RCSD1ABL2ID1831.pdf DOI: 10.4267/2042/70529 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

asparaginase and intrathecal therapy with Abstract methotrexate (8-week cycle) and produced a Review on t(1;1)(q24;q25)/inv(1)(q24q25), with morphologic remission but high-level minimal data on clinics, and the genes involved residual disease (MRD) was detected by flow Keywords cytometry. The patient received a hematopoietic stem cell RCSD1, ABL2, B-cell acute lymphoblatic leukemia transplant (total body irradiation and etoposide based preparative regimen) from an unrelated donor Clinics and pathology (Raca et al., 2015). The other case was treated Disease according to the ALL10-HR protocol. There was a good response to prednisone, and high MRD (Boer B-lymphoblastic leukemia, BCR-ABL1-like et al., 2017). (WHO, 2016). Epidemiology Evolution The 20-year-old case was in complete remission 8 Only 2 cases described: a 20-years-old man month post-transplant and with no evidence of (Roberts et al, 2014; Raca et al., 2015; Roberts et MRD (Raca et al., 2015). The other patient has al., 2017) and a second patient without further data been followed up for 3-4 years (Boer et al., 2017). (case A530 in Boer et al., 2017). These cases were first classified as B-ALL, and reclassified later as Prognosis "B-ALL, BCR-ABL1-like" after characterization The two cases showed a IKZF1 deletion. Roberts et [CHU1]of the RCSD1/ABL2 fusion. al. showed a tyrosine kinase inhibitors sensitivity The RCSD1/ABL2 case described by Roberts et al, when the RCSD1/ABL2 fusion was tested in Ba/F3 2014 was part of a study of 1665 B-ALL cases, cells and in vivo mice models, and dasatinib was three of which with ABL2 fusions. In the case proposed to be evaluated in the future treatment of described in Boer et al., 2017, the RCDS1/ABL2 BCR-ABL1-like B-ALL with ABL-class fusions, fusion case was identified in a series of 77 BCR- especially for RCSD1/ABL2 fusion)(Roberts et al, ABL1-like B-ALL cases. 2017) Treatment The 20-year-old case received induction therapy Cytogenetics with vincristine/peg- asparaginase/daunorubicin/prednisone with Cytogenetics morphological intrathecal cytorabine and methotrexate; there was This abnormality was not detected by conventional no response post induction at days 15 and 29). cytogenetic in any of the two cases. A complex Additional therapy included Cytoxan, cytarabine, 6- rearrangement necessarily occurs because the two mercaptopurine, decadron, vincristine, peg- genes are in opposite directions of transcription.

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 274 t(1;1)(q24;q25) RCSD1/ABL2 inv(1)(q24q25) RCSD1/ABL2 Gaillard B

Cytogenetics molecular Protein The rearrangement can be detected by molecular 1182 amino acids. ABL2 is also called ARG. ABL2 cytogenetics or other molecular technics. is a member of the ABL family of tyrosine kinases. ABL kinases have been found to play essential Genes involved and roles for the downstream signaling of the T- and B- cell receptors. ABL1 and ABL2 have both proteins overlapping and distinct functions. The two proteins diverge in their C-terminal halves: ABL2 RCSD1 contains two F-actin binding domains and a Location 1q24.2 microtubule-binding domain and is a key regulator Protein of actin cytoskeletal remodeling. ABL2 acts as 416 amino acids. RCSD1 is also called CAPZIP. negative regulator of signaling downstream of the CapZ-interacting protein, implication in kinase activity of the transmembrane receptor cytoskeleton regulation and cell migration. RCSD1 protein tyrosine kinase FLT3: it partially blocks is a mediator of non-canonical Wnt/JNK signalling. FLT3-induced AKT phosphorylation (Jacobsen et It interacts with the actin capping protein CapZ al., 2018; Kazi et al., 2017). ABL2 gene is often (CAPZA1, CAPZA2, CAPZB: capping actin implicated in solid tumors. protein of muscle Z-line subunits alpha 1, alpha 2 and beta). RCSD1 Binds CapZ to prevent CapZ Result of the chromosomal from binding to the actin cytoskeleton. The T-cell anomaly costimulatory receptor CD28 phosphorylation regulates RCSD1 (Hempel et al. 2017: Tian et al. Hybrid gene 2015). Description ABL2 5'RCSD1 (exon 3) - 3'ABL2 (exon 5). Location 1q25.2

Figure 1. RCSD1/ABL2 fusion protein, according to https://pecan.stjude.cloud/proteinpaint/ABL2

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 275 t(1;1)(q24;q25) RCSD1/ABL2 inv(1)(q24q25) RCSD1/ABL2 Gaillard B

Shah K, Gazi M, Nagaraj SR, Sun J, Chougule RA, Fusion protein Rönnstrand L. ABL2 suppresses FLT3-ITD-induced cell Description proliferation through negative regulation of AKT signaling. The transcript retains the tyrosine kinase domain of Oncotarget. 2017 Feb 14;8(7):12194-12202 ABL2 and a portion of the SH2 domain, but not the Raca G, Gurbuxani S, Zhang Z, Li Z, Sukhanova M, NH2-terminal SH3 domain (Raca et al., 2015). McNeer J, Stock W. RCSD1-ABL2 fusion resulting from a complex chromosomal rearrangement in high-risk B-cell acute lymphoblastic leukemia. Leuk Lymphoma. 2015 References Apr;56(4):1145-7 Yap KL, Furtado LV, Kiyotani K, Curran E, Stock W, Roberts KG, Yang YL, Payne-Turner D, Lin W, Files JK, McNeer JL, Kadri S, Segal JP, Nakamura Y, Le Beau MM, Dickerson K, Gu Z, Taunton J, Janke LJ, Chen T, Loh ML, Gurbuxani S, Raca G. Diagnostic evaluation of RNA Hunger SP, Mullighan CG. Oncogenic role and therapeutic sequencing for the detection of genetic abnormalities targeting of ABL-class and JAK-STAT activating kinase associated with Ph-like acute lymphoblastic leukemia alterations in Ph-like ALL. Blood Adv. 2017 Sep (ALL). Leuk Lymphoma. 2017 Apr;58(4):950-958 12;1(20):1657-1671 Hempel A, Kühl SJ, Rothe M, Rao Tata P, Sirbu IO, Vainio Tian R, Wang H, Gish GD, Petsalaki E, Pasculescu A, Shi SJ, Kühl M. The CapZ interacting protein Rcsd1 is required Y, Mollenauer M, Bagshaw RD, Yosef N, Hunter T, for cardiogenesis downstream of Wnt11a in Xenopus Gingras AC, Weiss A, Pawson T. Combinatorial proteomic laevis. Dev Biol. 2017 Apr 1;424(1):28-39 analysis of intercellular signaling applied to the CD28 T- cell costimulatory receptor. Proc Natl Acad Sci U S A. Jacobsen FA, Scherer AN, Mouritsen J, Bragadóttir H, 2015 Mar 31;112(13):E1594-603 Thomas Bäckström B, Sardar S, Holmberg D, Koleske AJ, Andersson Å. A Role for the Non-Receptor Tyrosine This article should be referenced as such: Kinase Abl2/Arg in Experimental Neuroinflammation. J Neuroimmune Pharmacol. 2018 Jun;13(2):265-276 Gaillard B. t(1;1)(q24;q25) RCSD1/ABL2 inv(1)(q24q25) RCSD1/ABL2. Atlas Genet Cytogenet Oncol Haematol. Kazi JU, Rupar K, Marhäll A, Moharram SA, Khanum F, 2019; 23(9):274-276.

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Leukaemia Section Short Communication

-20 or monosomy 20 Adriana Zamecnikova Kuwait Cancer Control Center, Kuwait [email protected]

Published in Atlas Database: April 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/mono20ID1079.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70530/04-2018-mono20ID1079.pdf DOI: 10.4267/2042/70530 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

unknown); most patients were diagnosed with Abstract refractory anemia with excess of blasts (RAEB) (68 patients), followed by myelodysplastic syndrome, Chromosome 20 anomalies are well-known in NOS (35 patients), refractory anemia (RA) (25 hematological malignancies, being del(20q) and patients), refractory cytopenia with multilineage dicentric chromosome 20 the most frequent. In dysplasia (12 patients) and refractory anemia with contrast, monosomy 20 that occurs in a variety of ringed sideroblasts (9 patients). Among them, 25 hematological neoplasms is less well characterized. patients developed MDS after chemotherapy and/or Keywords radiation therapy for previous tumors. Numerical chromosome anomalies, chromosome Acute myeloid leukaemia (AML): More than 400 20, del(20q), gene repression. patients with various AML types have been reported: 165 acute myeloid leukemia, NOS, 17 Clinics and pathology acute myeloblastic leukemia with minimal differentiation (AML-M0), 29 acute myeloblastic Disease leukemia without maturation (AML-M1), 71 acute Chronic and acute myeloid malignancies, myeloblastic leukemia with maturation (AML-M2), myelodysplastic syndromes (MDS), acute 5acute promyelocytic leukemia (AML- M3), 35 lymphoblastic leukemia (ALL) and plasma cell acute myelomonocytic leukemia (AML-M4), 16 neoplasms. acute monoblastic leukemia (AML-M5), 69 acute Etiology erythroleukemia (AML-M6) and 19 acute megakaryoblastic leukemia (AML-M7). The Detected in both myeloid and lymphoid estimated frequency of monosomy 20 in patients malignancies. with myeloid malignancies and abnormal Epidemiology karyotypes is about 11% (Raza et al., 2011). Chronic myeloproliferative disorder in 20 Lymphoid malignancies (9M/11F aged 29 to 80 years, median 65 years): 6 Acute lymphoblastic leukemia More than 450 myelofibrosis (MF), 6 polycythemia vera (PV), 3 reported patients; however up to half of these essential thrombocythemia (ET), 1 chronic patients had hyperdiploid/polyploid or hypodiploid myeloproliferative disorder (MPD), 1 MDS/MPD karyotypes with unknown significance of -20. The and there were 3 patients with chronic estimated frequency of isolated monosomy 20 in myelomonocytic leukemia. cytogenetically abnormal childhood ALL is about Chronic myeloid leukemia (CML) was diagnosed in 3% (Betts et al., 1990). 56 patients at different time points and disease Bilineage or biphenotypic leukemia (BAL) was stages (29M/27F aged 8 to 85 years, median 49 diagnosed in 9 patients (4M/5F aged 9 to 60 years, years). median 27 years). Myelodysplastic syndromes: 149 patients aged 1 Other malignancies Chronic lymphocytic to 84 years have been reported (99M/49F, 1 leukemia (CLL) in 44, T-prolymphocytic leukemia

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in 12 and about 200 patients with plasma cell In AML, monosomy 20 occurs in both noncomplex neoplasm. However, because monosomy 20 was and highly complex karyotypes, therefore the detected in various disease diseases stages in these presence of primary anomalies and the number of patients, it is unclear if its occurrence is related to additional anomalies may be a strong prognostic clonal evolution or to previous therapies and is a factor. In these patients, monosomy 20 frequently sign of therapy-related hidden myelodysplastic occurs as part of highly complex karyotypes with syndrome. combination of chromosome 5 and 7 abnormalities, Prognosis conferring unfavorable prognosis and poor response The presence of isolated monosomy 20 may be to chemotherapy. Isolated monosomy 20 in associated with premalignant haematological childhood ALL may indicate favorable prognosis conditions and an indolent clinical course in (Betts et al., 1990; Silengo et al., 1992) while in chronic myeloproliferative disorders with similar complex karyotypes the prognosis may depend on prognosis as in patients with del(20q). the presence of additional anomalies.

Figure 1. Karyotype and partial karyotypes showing monosomy of chromosome 20. Figure 2. True monosomy can be confirmed with the use of fluorescence in situ hybridization techniques applying locus specific LSI D20S108 (A) or chromosome 20 painting probes (Abbott Molecular/Vysis, US) showing (B).

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frequency of primary anomalies, being Cytogenetics t(9;22)(q34;q11) the most frequent, that has been detected in 35 B-ALL patients. Among them, -20 Identification of 20 monosomy in complex was detected as a sole additional anomaly to t(9;22) karyotypes or its combination with marker in 4 patients. Other primary anomalies were less chromosomes may be an indicator of unbalanced frequent, the t(1;19)(q23;p13) has been detected rearrangements, such as the dic(17;20) in myeloid only in 5 and t(4;11) in 2 patients. malignancy or dic(9;20) in acute lymphoid BAL: Found as part of complex karyotypes in leukaemia. Therefore, to confirm true monosomy association with t(9;22)(q34;q11) in 2 and with - 20, accurate karyotyping and the use of 5/del(5q) and/or -7/del(7q) in 4 out of 9 patients. fluorescence in situ hybridization techniques with locus specific or chromosome painting probes is Result of the chromosomal recommended. Because apparent monosomy 20 in complex karyotypes can be frequently anomaly misclassification of unbalanced chromosome 20 rearrangements, it is probably that true monosomy Fusion protein 20 is less frequent than it is reported. Oncogenesis Additional anomalies Monosomy 20 is a non-random chromosome abnormality that has been reported in a variety of Chronic myeloproliferative disorders: most patients hematological neoplasms, including had simple karyotypes and only 5 of them had myelodysplastic syndromes, acute myeloid highly complex aberrations; sole anomaly in 2, leukemia, Philadelphia chromosome-negative found in association with del(20q) in 3, +8 in 4, myeloproliferative neoplasms and acute del(5q)/-5 in 5, del(13q) in 2 and monosomy 7 in 2. lymhoblastic leukemia. Monosomy 20 results in CML: In 11 patients receiving tyrosine kinase haploinsufficiency of genes leading to a loss of inhibitor therapy or bone marrow transplant, expression, which may contribute to the monosomy 20 was detected in Philadelphia- development of malignancy. While the negative cells. Among them, it was a sole anomaly pathogenesis remains unknown, monosomy 20 is in 5 and in 4 it was found in association with presumed to remove tumor suppressors at 20q12, monosomy 22. Found as a sole additional anomaly the common deleted region of the well-known 20q tot(9;22) in 1 and with +der(22)t(9;22) in 21 deletion. Such candidate tumor suppressors may patients. include L3MBTL1 and SGK2 and their repression MDS: Sole anomaly in 1, found in a sideline may contribute to the development of malignancy 45,XY,-3/45,XY,-4/45,XY,-7/45,XY,-20 in 1; by inducing replicative stress, DNA damage, and found with, del(20),+mar in 1 and in a sideline with genomic instability. Isolated monosomy 20 could del(20)(q11) in 1. The majority of remaining be an early event, although additional events need patients had complex and highly complex to accumulate for cancer development, while in aberrations with monosomy 5/del(5q) and less complex karyotypes it is associated with unstable frequently chromosome 7 abnormalities or their clones reflecting disease evolution. combination. AML: Sole anomaly in 6, in 4 of them found in a References sideline. Rarely detected with well-known primary chromosome translocations; found in association Betts DR, Kingston JE, Dorey EL, Young BD, Webb D, with 4 t(9;22)(q34;q11) in 4, t(8;21)(q22;q22) in 2, Katz FE, Gibbons B. Monosomy 20: a nonrandom finding in childhood acute lymphoblastic leukemia. Genes inv(16)(p13q22)/t(16;16) in 2 and t(1;22)(p13;q13) Chromosomes Cancer. 1990 Sep;2(3):182-5 in 3 AML-M7 patients. Mainly found as a part of complex and highly complex karyotypes and Bonet C, Solé F, Woessner S, Florensa L, Besses C, Sans-Sabrafen J. A case of monosomy 20 in an adult unstable clones with frequent chromosome 5 and/or acute lymphoblastic leukemia. Cancer Genet Cytogenet. 7 abnormalities or both abnormalities together 1993 Sep;69(2):165 (about 2/3 of patients) and with commonly Clark R, Byatt SA, Bennett CF, Brama M, Martineau M, observed chromosomal abnormalities characteristic Moorman AV, Roberts K, Secker-Walker LM, Richards S, for myeloid malignancies such as +8 and 12p, 13q Eden OB, Goldstone AH, Harrison CJ. Monosomy 20 as a and 17p deletions and loss of a sex chromosome. pointer to dicentric (9;20) in acute lymphoblastic leukemia. ALL: Sole anomaly in 19 pediatric and 4 adult B- Leukemia. 2000 Feb;14(2):241-6 ALL patients; about half of patients presented with Gniot M, Lewandowski K, Ratajczak B, Lewandowska M, hyperdiploid (about 200 patients), polyploid (10 Lehmann-Kopydłowska A, Jarmuż-Szymczak M, Komarnicki M. Transient presence of clonal chromosomal patients) or hypodiploid (about 50 patients) aberrations in Ph-negative cells in patients with chronic karyotypes. The remaining patients presented myeloid leukemia remaining in deep molecular response mainly with complex karyotypes, with relative low on tyrosine kinase inhibitor treatment. Cancer Genet. 2014

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Oct-Dec;207(10-12):503-10 Raimondi SC, Krance RA, Mahmoud HH, Ribeiro RC, Sandlund JT, et al. L-asparaginase may potentiate the Heerema NA, Palmer CG, Baehner RL. Karyotypic and leukemogenic effect of the epipodophyllotoxins Leukemia clinical findings in a consecutive series of children with 1995 Oct;9(10):1680-4 acute lymphocytic leukemia Cancer Genet Cytogenet 1985 Jun;17(2):165-79 Pui CH, Williams DL, Raimondi SC, Rivera GK, Look AT, Dodge RK, George SL, Behm FG, Crist WM, Murphy SB. Heyman M, Grandér D, Bröndum-Nielsen K, Liu Y, Hypodiploidy is associated with a poor prognosis in Söderhäll S, Einhorn S. Deletions of the short arm of childhood acute lymphoblastic leukemia Blood 1987 chromosome 9, including the interferon-alpha/-beta Jul;70(1):247-53 genes, in acute lymphocytic leukemia Studies on loss of heterozygosity, parental origin of deleted genes and Raza S, TaherNazerHussain F, Patnaik M, Knudson R, prognosis Int J Cancer Van Dyke D, Tefferi A. Autosomal monosomies among 24,262 consecutive cytogenetic studies: prevalence, Jarosová M, Indrák K, Dusek J, Kapustová M. Cytogenetic chromosomal distribution and clinicopathologic correlates studies in polycythemia vera Neoplasma 1988;35(2):221-8 of sole abnormalities Am J Hematol 2011 Apr;86(4):353-6 Karrman K, Sallerfors B, Lenhoff S, Fioretos T, Johansson Russell M, List A, Greenberg P, Woodward S, Glinsmann B. Cytogenetic evolution patterns in CML post-SCT Bone B, Parganas E, Ihle J, Taetle R. Expression of EVI1 in Marrow Transplant 2007 Feb;39(3):165-71 myelodysplastic syndromes and other hematologic Katz JA, Taylor LD, Carroll A, Elder FF, Mahoney DH. malignancies without 3q26 translocations Blood 1994 Aug Cytogenetic features of childhood acute lymphoblastic 15;84(4):1243-8 leukemia A concordance study and a Pediatric Oncology Sánchez Fayos J, Pérez Rus G, Benitez J, Outeiriño J, Group study Cancer Genet Cytogenet Prieto E, Calabuig T, Pérez Sáenz MA, Rodríguez C, Kuchinskaya E, Heyman M, Grandér D, Linderholm M, Román A, Sánchez Castaña A. [Myelodysplastic Söderhäll S, Zaritskey A, Nordgren A, Porwit-Macdonald syndromes Hematologic phenotypes, cytogenetic A, Zueva E, Pawitan Y, Corcoran M, Nordenskjöld M, expression and clinical course in 133 cases (1979-1989)] Blennow E. Children and adults with acute lymphoblastic Sangre (Barc) leukaemia have similar gene expression profiles Eur J Safavi S, Hansson M, Karlsson K, Biloglav A, Johansson Haematol 2005 Jun;74(6):466-80 B, Paulsson K. Novel gene targets detected by genomic Li T, Xue Y, Zhang J, Chen S, Pan J, Wu Y, Wang Y, Shen profiling in a consecutive series of 126 adults with acute J. Isodicentric 20q- in two cases of B-cell acute lymphoblastic leukemia Haematologica 2015 lymphocytic leukemia with the respective t(9;20)(p11;q11 Jan;100(1):55-61 2) and t(9;22)(q34;q11 2) Silengo M, Vassallo E, Barisone E, Miniero R, Madon E. Li YS, Khalid G, Hayhoe FG. Correlation between Monosomy 20 in childhood acute lymphoblastic leukemia chromosomal pattern, cytological subtypes, response to Cancer Genet Cytogenet 1992 Apr;59(2):177-9 therapy, and survival in acute myeloid leukaemia Scand J Slater R, Smit E, Kroes W, Bellomo MJ, Mühlematter D, Haematol 1983 Mar;30(3):265-77 Harbott J, Behrendt H, Hählen K, Veerman AJ, Hagemeijer Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, A. A non-random chromosome abnormality found in El Kaffash DM, Coignet L, Nucifora G. AML1 gene over- precursor-B lineage acute lymphoblastic leukaemia: expression in childhood acute lymphoblastic leukemia dic(9;20)(p1?3;q11) Leukemia 1995 Oct;9(10):1613-9 Leukemia 2002 Apr;16(4):658-68 Walker A, Mrózek K, Kohlschmidt J, Rao KW, Pettenati Nakanishi M, Tanaka K, Shintani T, Takahashi T, Kamada MJ, Sterling LJ, Marcucci G, Carroll AJ, Bloomfield CD; N. Chromosomal instability in acute myelocytic leukemia Alliance for Clinical Trials in Oncology. New recurrent and myelodysplastic syndrome patients among atomic balanced translocations in acute myeloid leukemia and bomb survivors J Radiat Res 1999 Jun;40(2):159-67 myelodysplastic syndromes: cancer and leukemia group B 8461 Genes Chromosomes Cancer 2013 Apr;52(4):385- Poirel H, Radford-Weiss I, Rack K, Troussard X, Veil A, 401 Valensi F, Picard F, Guesnu M, Leboeuf D, Melle J, et al. Detection of the chromosome 16 CBF beta-MYH11 fusion Wang H, Jin J, Wang Y, Huang X, Huang J. Clonal transcript in myelomonocytic leukemias Blood 1995 Mar chromosomal abnormalities in Philadelphia-negative cells 1;85(5):1313-22 in chronic myeloid leukemia patients treated with nilotinib used in first-line therapy Ann Hematol 2013 Prigogina EL, Puchkova GP, Mayakova SA. Nonrandom Dec;92(12):1625-32 chromosomal abnormalities in acute lymphoblastic leukemia of childhood Cancer Genet Cytogenet 1988 Wilkens L, Tchinda J, Burkhardt D, Nolte M, Werner M, Jun;32(2):183-203 Georgii A. Analysis of hematologic diseases using conventional karyotyping, fluorescence in situ hybridization Pui CH, Behm FG, Raimondi SC, Dodge RK, George SL, (FISH), and comparative genomic hybridization (CGH) Rivera GK, Mirro J Jr, Kalwinsky DK, Dahl GV, Murphy SB. Hum Pathol 1998 Aug;29(8):833-9 Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia N Engl J Med 1989 Jul This article should be referenced as such: 20;321(3):136-42 Zamecnikova A. -20 or monosomy 20. Atlas Genet Pui CH, Relling MV, Behm FG, Hancock ML, Boyett JM, Cytogenet Oncol Haematol. 2019; 23(9):277-280.

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Leukaemia Section Review Ocular adnexal marginal zone lymphoma (OAMZL) Lucia Bongiovanni and Maurilio Ponzoni Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy. [email protected], [email protected]

Published in Atlas Database: November 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/OcularAdnexalMZLID1778.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70531/11-2018-OcularAdnexalMZLID1778.pdf DOI: 10.4267/2042/70531

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

hypothesis and in line with some extranodal Abstract marginal zone lymphomasarising in other Ocular adnexal marginal B-cell lymphoma anatomical sites, a pathogenetic model based on (OAMZL) is the most common type of primary chronic antigenic stimulation and acquired genetic lymphoma of this anatomical site. OAMZL is a rare alterations has been speculated for the occurrence entity, accounting for 1-2% of all non-Hodgkin of OAMZL. lymphomas. A pathogenetic link with chronic In particular, infection by Chlamydia psittaci (Cp) infection by Chlamydia psittaci has been has been related to OAMZL, even though with a demonstrated in some geographical areas. Because variable geographical distribution (Decaudin et al., of its rarity and the paucity of focused studies the 2008; Ferreri et al., 2008). clinical management of OAMZL is still The association between Cp and OAMZL has been controversial and uniform guidelines are not proved by PCR either on tumoral tissue, presently available. conjunctival swab and peripheral blood Keywords mononuclear cells using three different set of primers targeting distinct portions of the Cp Marginal zone lymphoma; MALT; Ocular adnexa; genome and, in selected cases, by laser-assisted Chlamydia psittaci. microdissection (Ponzoni et al., 2008). Direct demonstration of the microorganism in the Clinics and pathology cytoplasm of lymphoma-associated macrophages Phenotype/cell stem origin by immunohistochemistry has been validated by double immunofluorescence and electron The postulated normal counterpart is a post- microscopy besides on ex-vivo cultures (Ferreri et germinal centre marginal zone B cell (Swerdlow et al., 2004; Ferreri et al., 2008; Ferreri et al., 2009). al., 2016). Another important proof of a significant association Etiology between Cp and OAMZL is represented by the high The presence of native lymphoid mucosa associated rate of clinical responses obtained with anti-Cp lymphoid tissue (MALT) in the human orbital antibiotic treatment (Ferreri et al., 2012). region is still controversial. Some authors described A weak association between some autoimmune this tissue in the lamina propria of the conjunctiva diseases and the development of OAMZL has been and lacrimal drainage system of healthy individuals reported. (Knop and Knop, 2000). At a variance with this In particular Sjögren disease and autoimmune experience, some autoptic studies actually had thyroiditis showed a higher risk of periocular reported MALT only in the context of pathological lymphomas (Wöhrer et al., 2007; Nutting et al., conditions, mostly represented by conjunctivitis 2006). A recent study on patients with marginal (Wotherspoon et al., 1994). Following the latter zone lymphomas associated with autoimmune

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disorders showed a shorter median time to relapse Pathology and relapse-free survival in patients with OAMZL shares the morphological features of other autoimmune diathesis compared to patients without marginal zone lymphomas, characterized by small autoimmunity (Kleinstern et al., 2018). to medium size lymphocytes with centrocytic-like Epidemiology or monocytoid features and with a variabile OAMZL is a rare entity accounting for 1-2% of evidence of plasma cell differentiation; a minor non-Hodgkin lymphomas and 8% of all extranodal component of intermingled blasts resembling lymphomas with an incidence of about 0.28 person centroblasts or immunoblasts is recognized. for year (Moslehi et al., 2011). Scattered T-cells and secondary follicles with This lymphoma is usually observed in the reactive germinal centres accomplish neoplastic B- adulthood, with a median age of about 65 years, cells; follicles can be colonized (sometimes and a slight female prevalence (Ferry et al., 2007). mimicking follicular lymphoma) and/or eventually OAMZL is the most common orbital lymphoma, destroyed by malignant lymphocytes; these cells (80% of primary cases), followed by follicular can specifically infiltrate neighboring epithelia and lymphoma, diffuse large B-cell and mantle cell glands to form lymphoepithelial lesions, defined as lymphoma (Ferry et al., 2007). aggregates of ≥3 neoplastic B-cells. In OAMZL, lymphoepithelial lesions are detected most Clinics frequently in the lacrimal gland. Clinical presentation depends upon the affected The classic immunophenotype of OAMZL includes anatomical structure: the most common sites are the expression of B cell markers such as CD20, CD79a superior anterior orbit (40%) and conjunctiva (35- and PAX5, other molecules like bcl-2 and TCL-1, 40%), followed by the lacrimal gland (10-15%) and variable expression of CD43, CD11c and IRTA-1. the eyelids (10%). Bilateral involvement accounts Conversely CD5, CD10, CD23, cyclin D1, bcl-6 in about 10-15% of cases (Ferry et al., 2007; and MUM1 are negative, with few exceptions Kalogeropoulos et al., 2018). (Swerdlow et al., 2016; Sassone et al., 2017). OAMZL could be asymptomatic in the early Staining for CD23, CD21 or CD35 highlights phases. expanded and residual meshwork of follicular When symptomatic, it most commonly presents as dendritic cells. Neoplastic cells usually express IgM an intraorbital mass or less frequently as a and may also show immunoglobulin light-chain conjunctival lesion ("salmon red patch"). Frequent restriction. Cytoplasmic Cp-specific signs/symptoms include pain, irritation and lipopolysaccharide can be highlighted in the tumor- inflammation (sometimes mimicking associated macrophage cytoplasm by dacryoadenitis or dacryocystitis), epiphora, immunohistochemistry (Ferreri et al., 2004, exophalmos, diplopia, proptosis and loss of vision Ponzoni et al., 2008). Plasma cell differentiation (Ferreri et al., 2008). Since these symptoms are not may occur and sometimes can be prominent; rarely, specific, ocular biopsy is essential to achieve a plasma cells may express IgG4 (Kubota et al., definite diagnosis. 2010). Differential diagnosis encompasses non- Systemic staging and pre-treatment procedures, neoplastic lymphoproliferations, in particular including bone marrow biopsy, are perfomed. reactive lymphoid hyperplasia and IgG4-related In addition to usual procedures, complete peripheral disease. Distinction from reactive hyperplasia blood and biochemical profile as well as relies, in borderline cases, on the demonstration of investigation for infective agents are necessary monotypic immunoglobulin and eventually on among which Cp, Helicobacter pylori and hepatitis molecular studies for clonal rearrangement of the viruses (Sassone et al., 2017). immunoglobulin heavy chain gene (IgH), detectable Breath test followed by gastric biopsy to test by PCR in 55% of OAMZL. IgG4-related disease is Helicobacter pylori status is also indicated (Sassone a systemic disease characterized by elevated serum et al., 2017). Cp infection has to be assessed in IgG4 and infiltration of polytypic IgG4 plasma cells peripheral blood and conjunctival swabs by PCR. associated with reactive lymphoid follicles, Imaging analyses include MRI with enhancement phlebitis and fibrosis. Clinico-pathological of the orbit and adjacent structures, total-body CT correlation is critical for the recognition of this rare scan or PET/CT. entity.

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Ocular adnexal marginal zone lymphoma (OAMZL) Bongiovanni L, Ponzoni M

Figure 1. OAMZL of the conjunctiva showing the massive involvement of the lamina propria by neoplastic cells and the infiltration the epithelium above forming typical lymphoepithelial lesions (LELs), more evident with a 8/18 CK staining for epithelial cells (inset). Original magnification HE x200, inset x400.

Figure 2. Small to medium size neoplastic cells, with a prominent centrocytic-like appearance, admixed with scattered plasma cells and rare larger centroblastic-like cells. Original magnification x400.

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Figure 3. Neoplastic lymphocytes display a bright and diffuse CD20 staining. Immunostain for Chlamydia lipopolysaccharide shows scattered positive macrophages (inset). Original magnification x400; inset, x400.

Figure 4. Anti-CD23 staining for follicular dendritic cells highlights the remnant of a germinal centre (top left of the picture); neoplastic cells are CD23 negative. In the inset, the cells show a low proliferative index with a Ki-67 staining. Original magnification x200; inset, x200.

Treatment Radiotherapy, alone or in combination with chemotherapy, is the most common therapy. There are no uniform guidelines for the Reported outcomes are excellent, with local control management of OAMZL, therefore treatment rates of over 95%, 5 and 10-years DFS rates of strategies remain a matter of debate and linked to 84,65% and 78,7% and OS of 93,8% and 84,9% many patient- and lymphoma-related variables. respectively (Yen et al., 2018). The extension of the A watchful waiting approach, for example, can be radiation fields depends on the involved structures. useful for asymptomatic elderly patients with The International Lymphoma Radiation Oncology limited stage disease.

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Group suggested a radiation dose of 24-25 Gy Evolution provided in fractions of 1,5 to 1,8 Gy (Yahalom et OAMZL is an indolent disease, with a slow al., 2015). However, radiation toxicity effects are progression or stable disease without any treatment. distinct and well-known as well: early The median OS time is about 159 months (10-years complications are more frequently represented by OS 54,7%) in patients treated with radiotherapy in cutaneous and conjunctival reactions, while long- combination with chemotherapy, 103 months (10- term complications are radiation cataract, years OS 42,6%) in patients treated with retinopathy, optic neuropathy and xerophthalmia. chemotherapy only, 93 months (10-years OS Data on radioimmunotherapy are limited to few, 36,8%) in patients treated with radiotherapy only small studies, where OAMZL account for a and 60 months (32,5%) in patients without any minority of the studied cases (Sassone et al., 2017). treatment (Liu et al., 2018). Local recurrence is The use of antibiotics relies on the proven common, with 5-years relapse free survival rates of association with Cp infection. First-line 65%; recurrence in the contralateral orbit is a doxycycline monotherapy has been demonstrated to frequent event after radiotherapy. Systemic be well tolerated in a phase II trial study, with ORR dissemination is a rare event (5-10% of cases) of 65%, 5-year PFS of 61% and no significant side (Sassone et al., 2017; Martinet et al., 2003). effects (Ferreri et al., 2012). Antibiotics can also be used in Cp negative cases due to its off-target Prognosis effects. Clarithromycin, in particular, displays an There is no validated prognostic index for OAMZL. antitumor and immunomodulatory activity: a phase Recently, a MALT-IPI score based on the data of II trial in patients with relapsed/refractory the IELSG-19 trail and validated on a group of 633 OAMZLs achieved good responses with an ORR of patients, either with gastric and extra-gastric MALT 52% and a 2-year PFS of 56%, respectively (Ferreri lymphomas, has been introduced. et al., 2015). The score recognizes three distinct features with the Chemoimmunotherapy has been proposed as a good greatest prognostic significance in terms of event alternative to radiotherapy both in localized lesions free survival (EFS): age >70 years old, Ann-Arbor and in tumors extended beyond the conjunctiva or stage III or IV and elevated lactate dehydrogenase in bilateral disease (Ma et al., 2017). However, level. definitive data on efficacy of this strategy are still On these grounds, three prognostic groups with lacking, since most trials are retrospective or different 5-years EFS rates have been identified: considered a group of indolent lymphomas where low risk (70%), intermediate risk (56%) and high OAMZLs account only for a minor part of the risk (29%), respectively. The MALT-IPI score has cohort: the most frequently drugs tested in this been demonstrated to be a reliable scoring system setting are chlorambucil, bendamustin (with or for identification of patients with aggressive gastric without Rituximab), and purine analogs (Sassone et and extra-gastric lymphomas which could benefit of al., 2017). A recent phase II clinical trial with a different therapeutic approach (Thieblemont et al., rituximab, cyclophosphamide, vincristine and 2017). prednisone (R-CVP) in patients with bilateral, limited-stage OAMZL extending beyond- Genetics conjunctiva demonstrated a durable response and stressed the possibility and efficacy of a radiation- Marginal zone lymphomas share genetic alterations free upfront approach (93,9% CR at 2 years and and deregulations of some molecular pathways, but 90,3% of PFS at 4 years) with severe side effects also site-specific genetic profiles have been (neutropenia and hepatotoxicity) in a minority of uncovered in the last years. cases (12% and 6%, respectively) (Kim et al., 2017). Data on immunotherapy alone are few, Cytogenetics mainly focused on larger indolent NHL and extra- For OAMZLs, data on cytogenetic abnormalities gastric marginal lymphomas categories: a phase II are limited: trisomy of chromosome 3 (38-62%) trial in 18 patients with relapsed/refractory and 18 (14-47%) have been observed, and the latter extranodal MZL with Lenalidomide monotherapy has been associated with a higher risk of local obtained an ORR of 61% and manageable side- recurrence (Ferreri et al., 2008. Jung et al., 2017). effects; another study using Bortezomib in patients Copy number gain of 6p and 21q and copy number with newly diagnosed or relapsing/refractory loss of 6q and 9p have been described (Takahashi et MALT lymphoma showed good efficacy, with an al., 2015. Kwee et al., 2011). T(14;18)(q32;q21) ORR of 80%, but with relevant side effects IGH/ MALT1 is the most frequent chromosomal (Kiesewetter et al., 2013; Troch et al., translocation in OAMZLs (24% of cases); the Hematologica 2009). Finally, the management of t(11;18) BIRC3 (API2)/MALT1 is very rare (<3%) the relapsed patients lacks of consensus guidelines (Streubel, et al, 2003). as well.

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Ocular adnexal marginal zone lymphoma (OAMZL) Bongiovanni L, Ponzoni M

Genes involved and phase II trial. Ann Oncol. 2015;26:1760-5. Ferry JA, Fung CY, Zukerberg L. Lymphoma of the ocular proteins adnexa: A study of 353 cases. Am J Surg Pathol. 2007;31:170-84. Biased usage of IGHV genes with ongoing somatic Johansson P, Klein-Hitpass L, Grabellus F. Recurrent mutations points out the pathogenetic mechanism of mutations in NF-?B pathway components, KMT2D, and antigenic selection (Dagklis et al., 2012). NOTCH1/2 in ocular adnexal MALT-type marginal zone The most frequent immunoglobulin rearrangements lymphomas. Oncotarget. 2016;7:62627-62639. involve IGHV4-34 and IGHV3-23 families and are Jung H, Yoo HY, Lee SH. The mutational landscape of associated with auto-reactive B-cell receptors (Jung ocular marginal zone lymphoma identifies frequent et al., 2017). alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP. Oncotarget. 2017;8:17038-17049. A number of mutations leading to constitutive activation of NF-kB pathway, consequently Kalogeropoulos D, Papoudou-Bai A, Kanavaros P. Ocular promoting lymphocyte stimulation, proliferation adnexal marginal zone lymphoma of mucosa-associated lymphoid tissue. Clin Exp Med. 2018;18:151-163. and survival, have been detected in about 60% of the cases analyzed (Jung et al., 2017). Kim SY, Yang SW, Lee WS. Frontline treatment with chemoimmunotherapy for limited-stage ocular adnexal Among these, structural variations (deletions or MALT lymphoma with adverse factors: a phase II study. mutations) at 6q23.3 involving TNFAIP3 (A20), a Oncotarget. 2017;8:68583-68590. negative regulator of NF-kB, have been described Kleinstern G, Averbuch M, Abu Seir R. Presence of in 54% of cases in OAMZL; structural breakpoints autoimmune disease affects not only risk but also survival (deletions, intra-and inter-chromosomal in patients with B-cell non-Hodgkin lymphoma. Hematol translocations) in the same locus involving IL20RA Oncol. 2018;36:457-462. have also been found (Johansson et al., 2016; Jung Knop N, Knop E.. Conjunctiva-associated lymphoid tissue et al., 2017). The transcription regulator and in the human eye. Invest Ophthalmol Vis Sci. chromatin modifier TBL1XR1 is frequently 2000;41:1270-9. mutated (6-18%); loss of function mutations can Kubota T, Moritani S, Yoshino. Ocular adnexal marginal involve the chromatin modifiers CREBBP and zone B cell lymphoma infiltrated by IgG4-positive plasma KMT2D (Moody et al., 2017; Jung et al., 2017; cells. J Clin Pathol. 2010;63:1059-65. Johansson et al., 2016). MYD88 and rare BCL10 Kwee I, Rancoita PM, Rinaldi A. Genomic profiles of MALT mutations have been described in various reports lymphomas: variability across anatomical sites. (Cani et al., 2016; Jung et al., 2017). Recurrent Haematologica. 2011;96:1064-6. mutation of TP53 is evidenced even at a low Liu DL, Zheng ZJ.. Survival in B-cell primary ocular frequency. NOTCH1 and NOTCH2 mutations, lymphoma 1997-2014: a population-based study. J involved in B cell differentiation, have been Investig Med. 2018. pii: jim-2018-000758. described as well (Johansson et al., 2016; Jung et Ma WL, Yao M, Liao SL. Chemotherapy alone is an al., 2017). alternative treatment in treating localized primary ocular adnexal lymphomas. Oncotarget. 2017;8:81329-81342. Martinet S, Ozsahin M, Belkacémi Y. Outcome and References prognostic factors in orbital lymphoma: a Rare Cancer Network study on 90 consecutive patients treated with Cani AK, Soliman M, Hovelson DH, Liu CJ, McDaniel AS, radiotherapy. Int J Radiat Oncol Biol Phys. 2003;55:892-8. Haller MJ, Bratley JV, Rahrig SE, Li Q, Briceño CA, Tomlins SA, Rao RC. Comprehensive genomic profiling of Moody S, Escudero-Ibarz L, Wang M. Significant orbital and ocular adnexal lymphomas identifies frequent association between TNFAIP3 inactivation and biased alterations in MYD88 and chromatin modifiers: new routes immunoglobulin heavy chain variable region 4-34 usage in to targeted therapies. Mod Pathol. 2016 Jul;29(7):685-97 mucosa-associated lymphoid tissue lymphoma. J Pathol. 2017;243:3-8. Dagklis A, Ponzoni M, Govi S, Cangi MG, Pasini E, Charlotte F, Vino A, Doglioni C, Davì F, Lossos IS, Moslehi R, Coles FB, Schymura MJ. Descriptive Ntountas I, Papadaki T, Dolcetti R, Ferreri AJ, epidemiology of ophthalmic and ocular adnexal non- Stamatopoulos K, Ghia P. Immunoglobulin gene repertoire Hodgkin's lymphoma. Expert Rev Ophthalmol. 2011;6:175- in ocular adnexal lymphomas: hints on the nature of the 180. antigenic stimulation. Leukemia. 2012 Apr;26(4):814-21 Nutting CM, Shah-Desai S, Rose GE. Thyroid orbitopathy Decaudin D, Dolcetti R, de Cremoux P, Ponzoni M, possibly predisposes to late-onset of periocular lymphoma. Vincent-Salomon A, Doglioni C, Dendale R, Escande MC, Eye (Lond). 2006;20:645-8. Lumbroso-Le Rouic L, Ferreri AJ. Variable association between Chlamydophila psittaci infection and ocular Ponzoni M, Ferreri AJ, Guidoboni M. Chlamydia infection adnexal lymphomas: methodological biases or true and lymphomas: association beyond ocular adnexal geographical variations? Anticancer Drugs. 2008 lymphomas highlighted by multiple detection methods. Clin Sep;19(8):761-5 Cancer Res. 2008;14:5794-800. Ferreri AJ, Sassone M, Kiesewetter B. High-dose Sassone M, Ponzoni M, Ferreri AJ.. Ocular adnexal clarithromycin is an active monotherapy for patients with marginal zone lymphoma: Clinical presentation, relapsed/refractory extranodal marginal zone lymphoma of pathogenesis, diagnosis, prognosis, and treatment. Best mucosa-associated lymphoid tissue (MALT): the HD-K Pract Res Clin Haematol. 2017;30:118-130.

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Streubel B, Lamprecht A, Dierlamm J. T(14;18)(q32;q21) 2007;21:1812-8. involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood. 2003 Mar Wotherspoon AC, Hardman-Lea S, Isaacson PG.. 15;101(6):2335-9. Mucosa-associated lymphoid tissue (MALT) in the human conjunctiva. J Pathol. 1994;174:33-7. Swerdlow SH, Campo E, Pileri SA. The 2016 revision of the World Health Organization classification of lymphoid Yahalom J, Illidge T, Specht L. International Lymphoma neoplasms. Blood. 2016;127:2375-90. Radiation Oncology Group. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the Takahashi H, Usui Y, Ueda S. Genome-Wide Analysis of International Lymphoma Radiation Oncology Group. Int J Ocular Adnexal Lymphoproliferative Disorders Using High- Radiat Oncol Biol Phys. 2015;92:11-31. Resolution Single Nucleotide Polymorphism Array. Invest Ophthalmol Vis Sci. 2015;56:4156-65. Yen MT, Bilyk JR, Wladis EJ. Treatments for Ocular Adnexal Lymphoma: A Report by the American Academy Thieblemont C, Cascione L, Conconi A. A MALT of Ophthalmology. Ophthalmology. 2018;125:127-136. lymphoma prognostic index. Blood. 2017;130:1409-1417. This article should be referenced as such: Wöhrer S, Troch M, Streubel B. MALT lymphoma in patients with autoimmune diseases: a comparative Bongiovanni L, Ponzoni M. Ocular adnexal marginal zone analysis of characteristics and clinical course. Leukemia. lymphoma (OAMZL). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9):281-287.

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Leukaemia Section Short Communication t(1;5)(q21;q32) PDE4DIP/PDGFRB, t(1;5)(q21- 23;q32) TPM3/PDGFRB, t(1;5)(q21-23;q31-33) Adriana Zamecnikova Kuwait Cancer Control Center, Kuwait [email protected] Published in Atlas Database: July 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0105q22q33ID1115.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70532/07-2018-t0105q22q33ID1115.pdf DOI: 10.4267/2042/70532 This article is an update of : Huret JL. t(1;5)(q22;q33). Atlas Genet Cytogenet Oncol Haematol 2006;10(4)

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Clinics and pathology Chromosomal translocations involving chromosome bands 5q31-33 that contain the gene Disease encoding the platelet-derived growth factor beta Myeloproliferative disorders (MPD) with receptor (PDGFRB) are associated with a eosinophilia (or chronic eosinophilic leukemia significant minority of patients with BCR/ABL1- (CEL) and sporadic cases with acute myeloid negative chronic myeloid neoplasms. To date, leukemia (AML), B-cell acute lymphoblastic numerous PDGFRB fusion partners have been leukemia (ALL) or lymphoma. identified, with the vast majority being reported Phenotype/cell stem origin only in sporadic cases. Although PDGFRB fusions are rare, their identification is important in order to Phenotypically diverse myeloid neoplasms that identify patients in whom targeted therapy with include patients that have been categorized as: tyrosine kinase inhibitors is likely to be successful. chronic eosinophilic leukemia (CEL)/ atypical chronic myeloid leukemia with eosinophilia in 4 Keywords (Luciano et al., 1999; Rosati et al., 2006, Baxter et PDGFRB; PDE4DIP; TPM3; eosinophilia; al., 2003, Li et al., 2011), chronic myeloproliferative disorder; PDE4DIP/PDGFRB; myeloproliferative disorder (MPD) in 2 (Darbyshire TPM3/PDGFRB et al., 1987; Baxter et al., 2003), juvenile myelomonocytic leukemia (JMML) in 2, 1 of them Identity congenital JMML (Grainger et al., 2002 Abraham Note et al., 2010), chronic myeloid leukemia (CML) in 1 Included are reported patients with reciprocal 5q31- (Hild & Fonatsch.,1990), 5q33 translocations, with or without PDGFRB myelodysplastic/myeloproliferative disease in 1 involvement as patients with rearrangements of this (Wilkinson et al., 2003), refractory anemia with gene had translocations that appeared excess of blasts in 1 (RAEB) (Xu et al., 2010) and cytogenetically to involve bands from 5q31 to acute myeloid leukemia in 3 (Baxter et al., 2003; 5q33. Therefore, in patients with reciprocal Kern et al., 2002; Shearer et al., 2010). The translocation involving chromosome band 5q31-33 remaining cases were lymphoid malignancies: 5 B- it is important to identify involvement of PDGFRB cell ALL (Craig et al., 1990; Barriga et al., 1996; by molecular testing or by the use of dual color Coyaud et al., 2010; Safavi et al., 2015), 1 mantle break-apart probes that allows detection of cell lymphoma (MCL) (Le Baccon et al., 2001) and PDGFRB rearrangements before considering 1 diffuse large B-cell lymphoma (DLBCL) (Le targeted therapy. Baccon et al., 2001).

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Figure 1. Partial karyotypes with t(1;5)(q25;q33) (A). Fluorescence in situ hybridization with LSI 1p36/1q25 dual color probe (Vysis. Abott Molecular, US) showing the signal for 1q25 on der(1) chromosome (green signal) indicative of breakpoint distal to the probe (B). Hybridization with LSI 1p36/1q25 dual color and Kreatechô PDGFRB Break (Leica Biosystems, US) probes revealed PDGFRB remains on der(5) and is not disrupted by the translocation (C) - Courtesy Adriana Zamecnikova.

Epidemiology months from diagnosis (Darbyshire et al., 1987). The infant with PDE4DIP/PDGFRB fusion had Male prevalence (12 males and 7 females) aged 0 to refractory and progressive disease, but after therapy 79 years (median age 21 years) and notably, 5 with imatinib was started complete clinical and patients were infants (1 male and 3 females) hematologic remission, as well as major (Darbyshire et al., 1987; Wilkinson et al., 2003; cytogenetic response was achieved (Wilkinson et Grainger et al., 2002; Abraham et al., 2010) (Table al., 2003). 1 infant with JMML received autologous 1). Because the phenotypes are different, it may be stem cell transplantation after initial cytoreductive that genes involved in this/these disease(s) are not therapy failed to control the disease and is alive at similar; PDE4DIP and PDFRGB were found 10 years in full cytogenetic remission (Grainger et involved in MPD with eosinophilia (see below). al., 2002) and 1 with congenital JMML is alive 16+ Clinics months on imatinib therapy (Abraham et al., 2010). The 8-year-old male with CEL and Patients typically present with myeloproliferative TPM3/PDGFRB fusion had rapid hematologic neoplasm with eosinophilia and a spectrum of response and reduction of TPM3/PDGFRB morphologic presentations. Although eosinophilia transcripts after targeted therapy with imatinib (Li is characteristic of myeloid neoplasms associated et al., 2011). The 21-years old patient with CEL with PDGFRB rearrangement, marked eosinophilia obtained complete hematologic and major is not an invariable feature and the clinical cytogenetic response after two years of interferon presentation is variable. Patients are typically male therapy and is alive 7 years from diagnosis and while children are rarely affected with (Luciano et al., 1999). The other 21-years old male PDGFRB gene fusions, 6 out of 19 described with CEL and confirmed TPM3/PDGFRB fusion patients with t(1;5)(q21-23;q31-33) were children received interferon therapy for 10 years resulting in aged 0 to 13 years. major cytogenetic response and after continuing Prognosis with imatinib he achieved hematological, One of the infants with MPD died 9 month after cytogenetic and FISH remission (Rosati et al., diagnosis and the other remains well on therapy 14 2006).

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Ref Genes Sex/age Disease Karyotype Survival 19+ months, on 1 PDE4DIP/PDGFRB F/0 MPD 46,XX,t(1;5)(q23;q33) imatinib Therapy with interferon and 2 TPM3/PDGFRB M/21 CES 46,XY,t(1;5)(q21;q33) imatinib, alive 10+ years JMML from 1 year old; complete 3 TPM3/PDGFRB M/8 CEL t(1;5)(q21;q33) remission on imatinib, alive 8+ years? PDGFRB aCML/ 4 M t(1;5)(q21;q33) rearranged CEL PDGFRB 5 M MPD t(1;5)(q22;q31) rearranged PDGFRB 16+ months, on 6 M/0 JMML t(1;5)(q21;q33) rearranged imatinib No PDGFRB MDS/A 7 M t(1;5)(q21;q31) rearrangement ML 46,XX,add(1)(q?),t(9;22)(q34;q11) -- 8 ? F/31 CML > 46,XX,dup(1)(q23q32),t(9;22)/46,XX,t(1;5)(q21-22;q31),t(9;22) Alive after 9 ? F/0 JMML 46,XX,t(1;5)(q21;q33) BMT 10+ years 46,XY,t(8;21)(q22;q22) -- 10 ? M AML > 46,XY,t(1;5)(q21;q33),t(8;21)/46,idem,del(11)(p13) 45,XY,-7/46,idem,+21) --> 46-47,XY,inv(3)(q21q26),- 11 ? M/70 AML 7,+21,+mar/45,XY,inv(3),-7/45,XY,t(1;5)(q21;q31),inv(3),-7 RPN1/MECOM 12 ? M/51 B-ALL 46,XY,t(1;5)(q21;q31),del(9)(p12) 13 ? F/22 B-ALL 46,XX,t(1;5)(q21;q32)/42-48,idem,+8/48,idem,+der(5)t(1;5),+21 51,XX,add(1)(p12),t(1;5)(q21;q31),der(2)dup(2)(p16p25)t(1;2) DLBCL 14 ? F/67 (q21;q31),der(3)t(1;3)(p21;q22),der(4)t(4;11)(q35;q13),del(6)(p21), (LN) +del(7)(?q22?q34),del(8)(q24),add(11)(p12),+12,+21,+2mar died 9 month 15 ? F/0 MPD 46,XX,t(1;5)(q23;q33) after diagnosis Alive 14+ 16 ? M/0 MPD 46,XY,t(1;5)(q23;q33) months interferon 17 ? M/21 CEL 46,XY,t(1;5)(q23;q31) therapy, alive 7+ years 44,XX,t(1;5)(q23;q33),-7,der(12)t(7;12)(q?;p?)t(7;19)(q?;?),- 18 ? F/79 RAEB 18,der(19)t(11;19)(?;p11) Relapse after 3 months; CNS 19 ? M/13 B-ALL 46,XY,t(1;5)(q23;q33) relapse on day + 106 after BMT and died.

Abbreviations: M, male; F, female; MPD, Myeloproliferative disorder; CES; Chronic eosinophilic syndrome; CEL; Chronic eosinophilic leukemia; aCML, Atypical chronic myeloid leukemia; JMML, Juvenile myelomonocytic leukemia; MDS, myelodyslastic syndrome; AML; Acute myeloid leukemia; CML, Chronic myeloid leukemia; BMT, bone marrow transplantation; B-ALL, B-cell Acute lymphoblastic leukemia; DLBCL, Diffuse large B-cell lymphoma; LN, lymph node;, RAEB, Refractory anemia with excess of blasts. 1. Wilkinson et al., 2003; 2. Rosati et al., 2006; 3. Li et al., 2011; 4-5,7. Baxter et al., 2003; 6. Abraham et al., 2010; 8. Hild & Fonatsch.,1990; 9. Grainger et al., 2002; 10. Kern et al., 2002; 11. Shearer et al., 2010; 12. Coyaud et al., 2010; 13. Safavi et al., 2015;14. Le Baccon et al., 2001; 15-16. Darbyshire et al., 1987; 17. Luciano et al., 1999; 18. Xu et al., 2010; 19. Barriga et al., 1996.

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The 13-years-old boy with high-risk early pre-B Protein ALL underwent allogeneic bone marrow Member of the tropomyosin family of actin-binding transplantation after relapse but after a short second proteins that are dimers of coiled coil proteins; remission he had a central nervous system relapse binds and to actin filaments in muscle and non- and died (Barriga et al., 1996). muscle cells; mediates myosin-actin response to From these data, it appears that patients with calcium ions in skeletal muscles and regulates the t(1;5)(q21-23;q31-33) and PDGFRB rearrangement access to other actin-binding proteins; non-muscle have imatinib-responsive disease with durable isoform is found in cytoskeletal microfilaments remissions. (Rosati et al., 2006). Cytogenetics PDGFRB (platelet-derived growth factor receptor, beta polypeptide) Additional anomalies Location 5q32 Sole anomaly in 12 out of 19 described patients, Protein found in association with t(9;22)(q34;q11) in a PDGFRB is the receptor for PDGFB (platelet- sideline in CML (Hild & Fonatsch.,1990), derived growth factor-b); Ig like, transmembrane t(8;21)(q22;q22) in AML (Kern et al., 2002), and tyrosine kinase domains; membrane tyrosine del(9)(p12) in ALL (Coyaud et al., 2010), kinase; can homodimerize; activated in response to inv(3)(q21q26)/ -7 in AML (Shearer et al., 2010) ligand binding and receptor dimerization. and complex karyotypes in 3 patients (Le Baccon et al., 2001; Xu et al., 2010; Safavi et al., 2015). Result of the chromosomal Genes involved and anomaly proteins Hybrid gene Note Description Involvement of PDGFRB was demonstrated in PDE4DIP/PDGFRB. 5' PDE4DIP - 3' PDGFRB; several patients with t(1;5)(q21-23;q31-33) and PDE4DIP (KIAA0477 isoform) fuses in frame there has been two identified PDGFRB partner PDGFRB exon 11. The reciprocal PDGFRB- genes located at 1q21, PDE4DIP (Wilkinson et al., PDE4DIP is not expressed. 2003) and TPM3 (Rosati et al., 2006; Li et al., Description 2011). TPM3/PDGFRB. TPM3 fused exon 7 with exon 11 It is also possible that other genes from the 5q31- of the PDGFRB. A reciprocal fusion of exon 10 of q33 region such as TCOF1, CSF1R and CDX1 are PDGFRB to exon 8 has been detected (Rosati et al., potential translocation targets as well as IL3, IL5 2006). and CSF2 (GM-CSF) (cytokines involved in Fusion protein eosinophilopoiesis) may be dysregulated in the translocation process, at least in some patients. Description The first 905 amino acids of PDE4DIP, including PDE4DIP (phosphodiesterase 4D the coiled-coil domains are fused to the interacting protein (myomegalin)) transmembrane and the tyrosine kinase domains of Location 1q21.1 PDGFRB. Protein Oncogenesis PDE4DIP codes for a protein called myomegalin; Hematolymphoid neoplasms associated with interacts with the cyclic nucleotide PDGFRB gene fusions are infrequent and can be phosphodiesterase PDE4D; there are at least 2 observed in a wide range of hematological major isoforms of myomegalin in humans malignancies including myeloproliferative (KIAA0454 and KIAA0477), encoding N and C neoplasms with eosinophilia, atypical CML, Ph-like termini (Verde et al., 2001; Wilkinson et al., 2003); acute lymphoblastic leukemia and AML. myomegalin encodes several putative Genetically they are equally heterogeneous with at oligomerization domains capable of activating least 30 fusion genes having been described, PDGFRB. They include a leucine zipper (LZ) resulting from the formation of abnormal fusion domain and several coiled-coil structures. genes that encode constitutively activated tyrosine TPM3 (Tropomyosin 3 Tropomyosins kinases. While several PDGFRB partner genes remain to be characterized, constitutive activation TropomyosinsTropomyosinsTropom of protein tyrosine kinases is a common feature of yosins) neoplasms with fusion genes derived from Location 1q21.3 PDGFRB, triggering downstream signaling, but

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 291 t(1;5)(q21;q32) PDE4DIP/PDGFRB t(1;5)(q21-23;q32) Zamecnikova A TPM3/PDGFRB t(1;5)(q21-23;q31-33)

importantly they can be successfully targeted by pathogenesis of B-cell lymphoma and multiple myeloma tyrosine kinase inhibitors such as imatinib. Genes Chromosomes Cancer 2001 Nov;32(3):250-64 Li Z, Yang R, Zhao J, Yuan R, Lu Q, Li Q, Tse W. References Molecular diagnosis and targeted therapy of a pediatric chronic eosinophilic leukemia patient carrying TPM3- Abraham SM, Salama ME, Jacobsen JR, Hancock J, PDGFRB fusion Pediatr Blood Cancer 2011 Fluchel M.. Myeloid Neoplasm with PDGFRB Mar;56(3):463-6 Translocation, t(1;5)(q21;q33): A Congenital Presentation Luciano L, Catalano L, Sarrantonio C, Guerriero A, of An Imatinib Responsive Congenital JMML with Califano C, Rotoli B. AlphaIFN-induced hematologic and Eosinophilia. Blood 2010; 116:4092. cytogenetic remission in chronic eosinophilic leukemia with Barriga F, Bertin P, Legües E, Risueño C, Andrade W, t(1;5) Haematologica 1999 Jul;84(7):651-3 Cabrera E, Grebe G. t(1;5)(q23;q33) in a patient with high- Rosati R, La Starza R, Luciano L, Gorello P, Matteucci C, risk B-lineage acute lymphoblastic leukemia Cancer Genet Pierini V, Romoli S, Crescenzi B, Rotoli B, Martelli MF, Cytogenet 1996 Mar;87(1):4-6 Pane F, Mecucci C. TPM3/PDGFRB fusion transcript and Baxter EJ, Kulkarni S, Vizmanos JL, Jaju R, Martinelli G, its reciprocal in chronic eosinophilic leukemia Leukemia Testoni N, Hughes G, Salamanchuk Z, Calasanz MJ, 2006 Sep;20(9):1623-4 Lahortiga I, Pocock CF, Dang R, Fidler C, Wainscoat JS, Safavi S, Hansson M, Karlsson K, Biloglav A, Johansson Boultwood J, Cross NC. Novel translocations that disrupt B, Paulsson K. Novel gene targets detected by genomic the platelet-derived growth factor receptor beta (PDGFRB) profiling in a consecutive series of 126 adults with acute gene in BCR-ABL-negative chronic myeloproliferative lymphoblastic leukemia Haematologica 2015 disorders Br J Haematol 2003 Jan;120(2):251-6 Jan;100(1):55-61 Coyaud E, Struski S, Prade N, Familiades J, Eichner R, Shearer BM, Sukov WR, Flynn HC, Knudson RA, Quelen C, Bousquet M, Mugneret F, Talmant P, Pages Ketterling RP. Development of a dual-color, double fusion MP, Lefebvre C, Penther D, Lippert E, Nadal N, Taviaux S, FISH assay to detect RPN1/EVI1 gene fusion associated Poppe B, Luquet I, Baranger L, Eclache V, Radford I, Barin with inv(3), t(3;3), and ins(3;3) in patients with C, Mozziconacci MJ, Lafage-Pochitaloff M, Antoine-Poirel myelodysplasia and acute myeloid leukemia Am J Hematol H, Charrin C, Perot C, Terre C, Brousset P, Dastugue N, 2010 Aug;85(8):569-74 Broccardo C. Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti study Blood 2010 Apr 15;115(15):3089-97 D, Onuffer J, Jin SL, Conti M. Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic Darbyshire PJ, Shortland D, Swansbury GJ, Sadler J, nucleotide phosphodiesterase J Biol Chem 2001 Apr Lawler SD, Chessells JM. A myeloproliferative disease in 6;276(14):11189-98 two infants associated with eosinophilia and chromosome t(1;5) translocation Br J Haematol 1987 Aug;66(4):483-6 Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA, Aguiar RC. Cloning of the t(1;5)(q23;q33) in a Grainger JD, Will AM, Stevens RF. Cultured autografting myeloproliferative disorder associated with eosinophilia: for juvenile myelomonocytic leukaemia Br J Haematol involvement of PDGFRB and response to imatinib Blood 2002 May;117(2):477-9 2003 Dec 1;102(12):4187-90 Hild F, Fonatsch C. Cytogenetic peculiarities in chronic Xu W, Li JY, Liu Q, Zhu Y, Pan JL, Qiu HR, Xue YQ. myelogenous leukemia Cancer Genet Cytogenet 1990 Jul Multiplex fluorescence in situ hybridization in identifying 15;47(2):197-217 chromosome involvement of complex karyotypes in de Kern W, Haferlach T, Schnittger S, Ludwig WD, novo myelodysplastic syndromes and acute myeloid Hiddemann W, Schoch C. Karyotype instability between leukemia Int J Lab Hematol 2010 Feb;32(1 Pt 1):e86-95 diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy This article should be referenced as such: Leukemia 2002 Oct;16(10):2084-91 Zamecnikova A. t(1;5)(q21;q32) PDE4DIP/PDGFRB Le Baccon P, Leroux D, Dascalescu C, Duley S, Marais D, t(1;5)(q21-23;q32) TPM3/PDGFRB t(1;5)(q21-23;q31-33). Esmenjaud E, Sotto JJ, Callanan M. Novel evidence of a Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9):288- role for chromosome 1 pericentric heterochromatin in the 292.

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Leukaemia Section Short Communication t(4;12)(q21;p13) Tatiana Gindina R.M.Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation at FirstSaint-Petersburg State Medical University named I.P.Pavlov, Saint-Petersburg, Russia / [email protected]

Published in Atlas Database: September 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0412q21p13ID1504.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70533/07-2018-t0412q21p13ID1504.pdf DOI: 10.4267/2042/70533 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

AML. Abstract Acute lymphoblastic leukemia (ALL): was diagnosed in 5 patients (Groupe Franais de Review on t(4;12)(q21;p13) in lymphoid Cytogntique Hmatologique, 1993; Behm et al., malignancies 1996; Elghezal et al., 2001; Gindina T., own case, Keywords table 1,#8). Chromosome 4; Chromosome 12; Acute Primary mediastinal large-B-cell lymphoma was lymphoblastic leukemia; Primary mediastinal large found in 1 patient (Palanisamy et al, 2002) B-cell lymphoma; Adult T-cell Adult T-cell Leukemia: 1 patient (Sadamori et al., leukemia/lymphoma; Acute megakayoblastic 1991). leukemia. Non-Hodgkins lymphoma: 1 patient (Schouten et al., 1990). Acute myeloid leukemia: 1 patient with AML-M7 (Ohyashiki et al., 1984). Phenotype/cell stem origin Two patients had B-cell Early B ALL (CD10+) and Pre-B ALL (CIg +) (Groupe Franais de Cytogntique Hmatologique, 1993).

Figure 1. Partial karyotype with t(4;12)(q21;p13) in a Epidemiology female patient with B-ALL (table 1, #8). The translocation t(4;12)(q21;p13) was found in adults and children as well as equally among male Clinics and pathology and female patients. Disease Genetics Translocation t(4;12)(q21;p13) occurs predominantly in B-cell lymphoid disorders, Genes implicated in this translocation remain including ALL, NHL, rarely with T-ALL and unknown.

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 293 t(4;12)(q21;p13) Gindina T

Pts Disease Gender/Age Karyotype 49,XX, +3,+18,t(3;?)(q29;?), t(4;12)(q21;p13), 1 NHL F/? del(6)(q23),t(7;?)(q2l;?),t(9;?)(p23;?),t(14;18)(q32;q21),t(17;?)(p13;?),+mar 2 ATL M/? 48,XY,+del(l)(p32),+3,t(4;12)(q21;p13) 50,XX, dup(2)(q21q31),+3,t(4;12)(q21;p13), 3 PMBL F/? del(6)(q23),del(7)(q21),add(9)(p23),add(13)(p13),t(14;18)(q32;q21),+18, +add(20)(p13),+21 4 B-ALL F/? 47,XX,t(4;12)(q13;p12),del(15)(q14q25),+21,der(21) t(12;21)[3]/ 48,idem,+13[1]/49,idem,+X[1] B-ALL 5 Remission F/6 47,XX,t(1;12)(p22;p13),t(4;12)(q21;p13),+10, del(11)(q23)/45,X,-X,t(4;12) duration 30+ 6 B-ALL M/3 47,XY,del(1q),del(2q),der(3q), t(4;12)(q13;p12), del(6)(q21q25), + mar 7 B-ALL M/5 46, XY, der(1)t(1;?)(p36;?), t(4;12)(q13;p12) 8 B-ALL F/3 48,XX,t(4;12)(q21;p13),+10,+21 9 AML-M7 M/59 46,XY,t(4;12)(q21;p13) Table 1. Reported cases with t(4;12)(q21;p13). NHL: non-Hodgkin's lymphoma; ATL: Adult T-cell leukemia; PMBL: Primary mediastinal large-B-cell lymphoma; B-ALL: B-Acute lymphoblastic leukemia; AML-M7: Acute megakaryoblastic leukemia 1. Schouten et al., 1990: 2. Sadamori et al., 1991; 3. Palanisamy et al., 2002; 4. Elghezal et al., 2001; 5. Behm et al., 1996; 6,7. Groupe Franais de Cytogntique Hmatologique, 1993; 8. Gindina, personal observation; 9. Ohyashiki et al., 1984.

Cytogenetics References Additional anomalies Behm FG, Raimondi SC, Frestedt JL, Liu Q, Crist WM, Additional chromosome abnormalities were Downing JR, Rivera GK, Kersey JH, Pui CH. Rearrangement of the MLL gene confers a poor prognosis observed in all these patients with lymphoid in childhood acute lymphoblastic leukemia, regardless of malignancies. Translocation t(4;12) was associated presenting age. Blood. 1996 Apr 1;87(7):2870-7 with such anomaly as translocation Collaborative study of karyotypes in childhood acute t(14;18)(q32;q21) in 2 cases (Schouten et al., 1990; lymphoblastic leukemias. Groupe Français de Palanisamy et al., 2002) and translocation Cytogénétique Hématologique. Leukemia. 1993 t(12;21)(p13;q22) ETV6/ RUNX1 in 1 patient Jan;7(1):10-9 (Elghezal et al., 2001). Elghezal H, Le Guyader G, Radford-Weiss I, Perot C, Van Trisomies of chromosomes 3 and 21 were present Den Akker J, Eydoux P, Vekemans M, Romana SP. in 3 patients each (Schouten et al., 1990, Sadamori Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis. Genes et al., 1991; Palanisamy et al., 2002; and Chromosomes Cancer. 2001 Apr;30(4):383-92 Palanisamy et al., 2002; Elghezal et al., 2001; Gindina T. own case #8, respectively), trisomies of Ohyashiki K. Nonrandom cytogenetic changes in human acute leukemia and their clinical implications Cancer chromosomes 10 and 18 were in 2 cases each Genet Cytogenet 1984 Apr;11(4):453-71 (Behm et al., 1996; Gindina T. own case #8, respectively and Schouten et al., 1990; Palanisamy Palanisamy N, Abou-Elella AA, Chaganti SR, Houldsworth J, Offit K, Louie DC, Terayu-Feldstein J, Cigudosa JC, Rao et al., 2002, respectively). Deletion of 6q was PH, Sanger WG, Weisenburger DD, Chaganti RS. Similar demonstrated in 3 patients (Schouten et al., 1990; patterns of genomic alterations characterize primary Palanisamy et al., 2002; Groupe Franais de mediastinal large-B-cell lymphoma and diffuse large-B-cell Cytogntique Hmatologique, 1993). In most cases, lymphoma Genes Chromosomes Cancer 2002 Feb;33(2):114-22 t(4;12)(q21;p13) was as a part of a complex karyotype. As a single anomaly, t(4;12)(q21;p13) Sadamori N, Isobe M, Shimizu S, Yamamori T, Itoyama T, Ikeda S, Yamada Y, Ichimaru M. Relationship between was described only in one case of AML (Ohyashiki chromosomal breakpoint and molecular rearrangement of et al., 1984). T-cell antigen receptors in adult T-cell leukaemia Acta Haematol 1991;86(1):14-9 Result of the chromosomal Schouten HC, Sanger WG, Weisenburger DD, Armitage JO. Abnormalities involving chromosome 6 in newly anomaly diagnosed patients with non-Hodgkin's lymphoma Nebraska Lymphoma Study Group Cancer Genet Fusion protein Cytogenet

Oncogenesis This article should be referenced as such: Most likely, the translocation t(4;12)(q21;p13) is a secondary genetic event in oncogenesis. Gindina T. t(4;12)(q21;p13). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9):293-294.

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Leukaemia Section Short Communication t(20;21)(q11;q22) RUNX1/NOL4L Jean-Loup Huret [email protected]

Published in Atlas Database: October 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t2021q11q22ID1307.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70534/10-2018-t2021q11q22ID1307.pdf DOI: 10.4267/2042/70534 This article is an update of : Huret JL. t(20;21)(q11;q22). Atlas Genet Cytogenet Oncol Haematol 2009;13(3)

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monosomy 7 in another case, and t(9;22)(q34;q11) Abstract in the remaining case. Review on t(20;21)(q11;q22), with data on clinics, and the genes involved. Genes involved and Keywords Chromosome 20; Chromosome 21; Acute myeloid proteins leukemia; Chronic myelogenous leukaemia; NOL4L (nucleolar protein 4 like) RUNX1. NOL4L Location 20q11.2 Clinics and pathology DNA/RNA 11 exons Disease Protein Acute myeloid leukaemia (AML) without Nothing is known concerning the domains of the maturation (M1- AML) in one case, AML with protein, nor it's function. maturation (M2-AML) in one case; and blast crisis of myeloid type of chronic myelogenous leukaemia RUNX1 (runt-related transcription in two cases. factor 1 (acute myeloid leukemia 1; Epidemiology aml1 oncogene)) Four cases available to date; three with Location 21q22.12 t(20;21)(q11;q22) RUNX1/? (Misawa et al. 1986; Protein Dube et al., 1989; Jeandidier et al., 2006), and one RUNX1, also called AML1 or CBFA2, contains a case with proved t(20;21)(q11.2;q22.1) Runt domain and, in the C-term, a transactivation RUNX1/NOL4L (Guastadisegni et al. 2010). They domain, an inhibition domain, and various were all male patients, aged aged 44, 57, 67, and 72 regulatory regions; forms heterodimers; widely years. expressed; nuclear localization. RUNX1 is a transcription factor, critical regulator Cytogenetics of hematopoietic-cell development. It binds to the core site 5' PyGPyGGTPy 3' of Additional anomalies promotors and enhancers. No additional anomaly in one case, monosomy 5 RUNX1 is involved in many de novo and treatment and major karyotypic anomalies in one case, related leukemias.

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 295 t(20;21)(q11;q22) RUNX1/NOL4L Huret JL

patients with hematopoietic disorders: a collaborative Result of the chromosomal retrospective study of the Groupe Français de Cytogénétique Hématologique. Cancer Genet Cytogenet. anomaly 2006 Apr 1;166(1):1-11 Hybrid gene Calabrese G, Fantasia D, Franch PG, Morizio E, Stuppia L, Gatta V, Olioso P, Mingarelli R, Spadano A, Palka G. Description Spectral karyotyping (SKY) refinement of a complex RUNX1 exon 6 was fused to NOL4L exon 8 in the karyotype with t(20;21) in a Ph-positive CML patient submitted to peripheral blood stem cell transplantation. case reported by Guastadisegni et al. 2010. Bone Marrow Transplant. 2000 Nov;26(10):1125-7 Fusion protein Dubé I, Dixon J, Beckett T, Grossman A, Weinstein M, Oncogenesis Benn P, McKeithan T, Norman C, Pinkerton P. Location of breakpoints within the major breakpoint cluster region (bcr) Wild-type NOL4L was expressed at low levels in in 33 patients with bcr rearrangement-positive chronic AML and normal bone marrow, whereas the myeloid leukemia (CML) with complex or absent RUNX1/NOL4L was expressed at high levels Philadelphia chromosomes. Genes Chromosomes Cancer. (Guastadisegni et al. 2010). 1989 Sep;1(1):106-11 Misawa S, Hogge DE, Oguma N, Wiernik PH, Testa JR.. References Detection of clonal karyotypic abnormalities in most patients with acute nonlymphocytic leukemia examined Jeandidier E, Dastugue N, Mugneret F, Lafage-Pochitaloff using short-term culture techniques. Cancer Genet M, Mozziconacci MJ, Herens C, Michaux L, Verellen- Cytogenet. 1986 Jul;22(3):239-51. Dumoulin C, Talmant P, Cornillet-Lefebvre P, Luquet I, Charrin C, Barin C, Collonge-Rame MA, Pérot C, Van den This article should be referenced as such: Akker J, Grégoire MJ, Jonveaux P, Baranger L, Eclache- Huret JL. t(20;21)(q11;q22) RUNX1/NOL4L. Atlas Genet Saudreau V, Pagès MP, Cabrol C, Terré C, Berger R. Cytogenet Oncol Haematol. 2019; 23(9):295-296. Abnormalities of the long arm of chromosome 21 in 107

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Solid Tumour Section Short Communication

Kidney: Succinate dehydrogenase-deficient renal cell carcinoma Paola Dal Cin Department of Pathology, Brigham and Women's Hospital, Boston, MA. [email protected]

Published in Atlas Database: January 2019 Online updated version : http://AtlasGeneticsOncology.org/Tumors/SDHdeficientRenalCellCarcID6984.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70535/01-2019-SDHdeficientRenalCellCarcID6984.pdf DOI: 10.4267/2042/70535 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

of eosinophilic, typically low grade tumor cells that Abstract have a bubbly appearance due to the presence of Short communication on succinate dehydrogenase- cytoplasmic vacuoles (abnormal mitochondria deficient renal cell carcinoma. secondary to the SDH mutation); the latter may be Keywords lost in higher-grade transformed tumors. Immunohistochemistry All cases with the typical Kidney; Renal cell carcinoma morphology demonstrated negative staining for SDHB. Identity The presence of negative staining for SDHB almost Other names always signifies germline mutation of one of the Kidney: SDH-deficient renal cell carcinoma components of the mitochondrial complex 2 (SDHA, SDHB, SDHC, SDHD, SDHAF2) Clinics and pathology Prognosis Epidemiology Sarcomatoid changes and necrosis are rare but are Succinate dehydrogenase-deficient renal cell associated with poorer outcomes. carcinoma represents between 0.05 and 0.2% of all renal cell carcinoma (RCCs) and is found in young Genetics adults. Mean patient age at presentation was 37 Two hit process years (range, 14 to 76 y), with a slight male The two hit process (germ line mutations and loss predominance (M:F=1.7:1). of the wild-type allele) is involved in the Clinics development of SDHB-deficient renal cell Bilateral tumors were observed in 26% of patients. carcinoma (Schmidt and Linehan 2016). Patients with germ line mutations in succinate The risk of renal tumors seems highest for SDHB dehydrogenase deficient (SDH) subunit genes mutation. (SDHA ,B,C and D) are highly sensitive to certain The germ line mutations reported were extensively types of neoplasms such as paragangliomas, found in exons coding the mitochondrial targeting pheochromocytomas, gastrointestinal stromal sequence or 2FE-2S ferredoxin-type iron-sulfur tumorsand renal cell carcinomas (Gill AJ .2012). binding domain. Next-generation sequencing data Additionally, a Pathology targeted next-generation sequencing panel did not Tumors have a tan to light brown well reveal alterations in other key genes involved in circumscribed cut surface. SDH-deficient RCC RCC pathogenesis, such as VHL, PIK3CA, AKT, cells are comprised of a monomorphic population MTOR, MET, or TP53 (Williamson et al. 2015).

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9) 297 Kidney: Succinate dehydrogenase-deficient renal cell Dal Cin P carcinoma

Genes involved and References proteins de Soet JJ, van Dalen PJ, Pavicic MJ, de Graaff J. Enumeration of mutans streptococci in clinical samples by Succinate dehydrogenase (SDH) using monoclonal antibodies. J Clin Microbiol. 1990 Nov;28(11):2467-72 genes; SDHA, SDHB, SDHC, SDHD, Schmidt LS, Linehan WM. Genetic predisposition to kidney SDHAF2. cancer. Semin Oncol. 2016 Oct;43(5):566-574 Succinate dehydrogenase (SDH) is a key Williamson SR, Eble JN, Amin MB, Gupta NS, Smith SC, respiratory enzyme complex that converts succinate Sholl LM, Montironi R, Hirsch MS, Hornick JL. Succinate to fumarate in the citric acid cycle (CAC) and also dehydrogenase-deficient renal cell carcinoma: detailed functions in the mitochondrial electron transport characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod Pathol. 2015 Jan;28(1):80-94 chain. It comprises 4 subunits, SDHA, SDHB, SDHC, and This article should be referenced as such: SDHD Dal Cin P. Kidney: Succinate dehydrogenase-deficient renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(9):297-298.

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