Number 11 November 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Volume 1 - Number 1 May - September 1997

Volume 21 - Number 11 November 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

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

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

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

Editorial correspondance

Jean-Loup Huret, MD, PhD, Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France phone +33 5 49 44 45 46 [email protected]

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

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

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

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

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

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

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants Franck Viguié Malades, 75015 Paris, France; [email protected]

Volume 21, Number 11, November 2017

Table of contents

Gene Section

PGR (progesterone receptor) 389 Gajanan Sherbet WNT10B (wingless-type MMTV integration site family) 398 Alessandro Beghini, Francesca Lazzaroni

Leukaemia Section

Acute myeloid leukemia with myelodysplasia related changes 404 Alexandra Nagy, Andreas Neubauer dic(9;12)(p13;p13) PAX5/ETV6 409 Jean-Loup Huret i(7)(q10) 414 Anwar N Mohamed Aggressive natural killer leukemia (ANKL) 418 Anwar N Mohamed del(6q) 421 Anwar N. Mohamed

Solid Tumour Section

Breast: carcinoma with t(1;3)(p36;q13) PRDM16/BBX 429 Jean-Loup Huret Kidney: Renal cell carcinoma with t(X;17)(p11;q25) ASPSCR1/TFE3 431 Pedram Argani, Marc Ladanyi

Case Report Section

A new case of acute lymphoblastic leukemia with der(X)t(X;8)(q28;q11.2) 434 Tatiana Gindina, Nikolay Mamayev, Vadim Baykov, Olga Slesarchuk, Tatiana Rudakova, Elena Babenko, Boris Afanasyev

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Gene Section Review

PGR (progesterone receptor) Gajanan Sherbet School of Electrical and Electronic Engineering, University of Newcastle Upon Tyne, Newcastle Upon Tyne UK and the Institute for Molecular Medicine, Huntington Beach CA, USA; [email protected]; [email protected] Published in Atlas Database: February 2017 Online updated version : http://AtlasGeneticsOncology.org/Genes/PGRID41700ch11q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68995/02-2017-PGRID41700ch11q22.pdf DOI: 10.4267/2042/68995 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Many SNPs have been identified, mostly Abstract inconsequential ones. Some may be related to breast, The progesterone receptor gene PGR is located on endometrial and colorectal cancer risk. PR produces 11q22.1. The functional gene has 8 exons and 7 good clinical outcome in breast cancer introns; the transcript is translated into 933 residues. independently of ER. It displays greater correlation The protein occurs as three isoforms viz. PR-A; PR- than ER with disease progression and prognosis. It B; PR-C and 11 splice variants. PR-A and PR-B are may be differentially expressed in benign prostatic structurally similar. The function of the splice hyperplasia and progressive cancer. The expression variants is unclear, although some variants might be may reflect androgen-insensitivity. PROGINS is translated and others differentially expressed. The said to increase ovarian cancer risk, but, nuclear receptor PR isoforms are ubiquitously and paradoxically, reduce breast cancer risk. The use of uniformly expressed in target tissues. They may progesterone antagonists or agonists has been show differential expression in neoplasia with advocated. PRs can act as activators or repressors of progressive changes. In the conventional pathway, transcription, necessitating the identification of the PR undergoes conformational changes upon ligand functional PR/ER isoforms. Some new progestins, interaction, translocates into the nucleus and binds employed in HRT, have been claimed to prevent PREs of responsive genes. PR can also function by certain forms of cancer. non-genomic mode. It can activate the extra nuclear Keywords receptors, mPRs and PGRMC1 to influence cell Apoptosis; Breast cancer , Cancer prevention; proliferation and invasion via non-canonically Cancer progression and prognosis; Canonical routes. Both genomic and non-genomic modes of signalling; Cell adhesion; Cell proliferation; signaling may determine the relevance and the Extranuclear receptors; Growth factor/PI3K/Akt/ validity of PR in the progression, prognosis and MAPK; Isoforms; mPRs; Non-genomic signalling; management of breast cancer. The PR engages Ovarian cancer; Polymorphism; Progesterone several systems, among them are PI3K/Akt/ MAPK antagonists/agonists; Progesterone receptor gene; and Wnt to influence cell adhesion, proliferation and PROGINS; Splice variants; Wnt signalling apoptosis. The ER/PR axis is crucial in breast cancer, where the physiological outcome would be affected Identity by the differential signaling initiated by the canonical and the non-canonical receptors. The Other names: PR, NR3C3 crosstalk between the ER/PR axis and the growth HGNC (Hugo): PGR factor/PI3K/Akt/mTOR system is also highly Location : 11q22.1 relevant. PGR mutations and polymorphism are infrequent in cancers. The polymorphic PROGINS Location (base pair) has been linked, not indisputably, with cancer risk. Start: 101,029,624 bp end:101,130,524 bp reverse strand.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 389 PGR (progesterone receptor) Sherbet GV

Figure 1: Diagrammatic representation of 11q22.1 with PGR together with local gene sequence. CNTN5: Contactin 5; ARHGAP42: RhoGTPase Activating Protein; PGR: Progesterone Receptor; TRCP: Transient Receptor Potential Cation Channel Subfamily C Member 6; ANGPTL5: Angiopoietin-like Protein 5; CEP126: Centrosomal Protein 12; YAP1: Yes-associated protein 1 of the Hippo signalling system

Figure 2: The figures shows PGR-001 transcript ENST00000325455.9 (not drawn to scale).

separate promoters and translational start sites to DNA/RNA produce the two principle PR isoforms PR-A (94 Description kDa) and PR-B (118 kDa). The isoforms contain a DNA binding domain and a ligand binding domain. The functional PGR gene has 8 exons and 7 introns. N-terminal to the DBD is an AF-1 (activation The 13,748 bps transcript is translated into 933 function -1) and in the C-terminal direction a nuclear residues The gene has 11 splice variants. It uses localisation signal and the LBD containing AF-2. separate promoters and translational start sites in The PR-B isoform has a 164 aminoacid stretch at the Exon 1 to produce two principal isoforms, PR-A and N-terminus with an AF-3 (Figure 3c). It is believed PR-B that AF-1 is thought to mediate ligand-independent (http://grch37.ensembl.org/Homo_sapiens/Gene/Su activity, whilst AF-2 is attributed wih ligand- mmary?g=ENSG00000082175;r=11:100900355- dependent PR activation. The N-terminal inhibitory 101001255). subdomain of ?155 amino acids is not shown; The inhibitory domain does not function in the PR-B Protein isoform. AF-1 is about 456-546. Description The third isoform is the splice variant PR-C. PR-C The isoforms PR-A and PR-B are the products of a can bind the ligand, but in the absence of the DBD single gene. The top Figure 3 shows the use of would not be able to bind to PREs of target genes.

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Figure 3: A and B reproduced from Li X, O'Malley B. (2003) by permission from Dr B. O'Malley. [email protected]. Figure C is based on Wardell et al. (2005). The dimensions of the domain are not drawn to scale. The domain structure of PR isoforms. DBD: DNA binding domain; LBD: Ligand binding domain; AF-3, AF-1, AF-2: Activation domains

Alternatively spliced variants induces high mitotic activity in the epithelium and Many truncated splice variants of PR are generated the stroma. and these are not easily detected by standard anti-PR The secretory phase is characterised by the action of antibodies (Cork et al. 2012) and often specimens progesterone towards the differentiation of the may be designated as PR-negative. However, in the endometrium. absence of firm evidence that these are functionally It ought to be pointed out here that the PR delta 4/6 relevant in the cancer process, the inability to detect showed a slight difference in expression between them may not be of much consequence. 1/45 normal and 5/45 breast cancer tissues of the Besides the three major isoforms, several splice patients (Nagao et al. 2003). Whilst reports of variants of the gene have been identified. These are deletion variants are many, some earlier work has a result of the deletion of some of the eight exons of claimed the detection of insertion variants. One such PR or by the retention of intronic sequences (see is a variant with a 232 bp nucleotide insertion Cork et al. 2008). Two variants were translated into sequence between exons 4 and 5 in normal protein and were found to be differentially expressed endometrium (Yamanaka et al. 2002). However, in in the endometrium (Springwald et al. 2010). the absence of information whether the variant However, the functional status of the variants is transcript is translated, the inference of a potential unclear. Variants with the deletion of exons 4, 6 and relevance in normal or pathological condition of the 4/6 (delta exons), and another one with partly deleted endometrium is not warranted. exon 6 have been identified. Their expression was Splice variants: PR-delta4, PR-delta6, PR-delta6/7, higher in early/mid proliferative endometrium than PR-T, PR-S, PR-M, PR-i45 (insertion variant) i45a in the secretory phase (Marshburn et al. 2005). and i45b. This suggests that they might be functionally not relevant. For, in the proliferative phase oestrogen

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Figure 4: Figure 4 shows the effects of the canonical and non-canonical oestrogen receptor signalling. The isoforms can act as activators or repressors of transcription. PR-A is a ligand dependent repressor of PR-B. The PR-A and PR-B isoforms regulate different sets of target genes. The PR-B isoform is associated with increase in cell migration but not on cell proliferation or survival. PR-B activates many progesterone response genes by activating Src/MAPK signalling pathways, which can promote or inhibit cell proliferation (see also legend below). Progesterone induces endometrial proliferation and angiogenesis via the VEGF route. Both mPR and PGRMC1 can directly interact with progesterone and function independently of PR. PGRMC1 is also able to induce physiological effects by interaction with EGFR. Some of these pathways are not shown here. PGRMC1 : Progesterone receptor membrane component 1.

Expression can directly interact with progesterone even in the absence of PR. The present indications are that both PR is expressed ubiquitously in human tissues as increase cell proliferation and migration. In fact, homo- or heterodimers. The isoforms are expressed PGRMC1 may also facilitate cell proliferation and in relatively equal abundance in most target tissues. tumour growth. A small molecule inhibitor of In the event of neoplastic transformation, the PGRMC1 counteracts these effects. This inhibitor isoforms might be differentially expressed and also destabilises EGFR expression, which would display progressive changes (see Scarpin et al. suggest that the PGRMC1 effects are to mediated by 2009). interaction with EGFR (Ahmed et al. 2010a, b). Function Although cell proliferative signalling does seem to be modulated by mPRs and the PGRMC1, there is a Function and Signalling need to resolve whether mPRs and PGRMC1 work Progesterone signalling generates its physiological in the same phenotypic direction or exert opposing effects by the conventional canonical nuclear effects. Recent developments make it imperative that receptor (PR) pathway and also by the seven-pass the non-canonical mode of progesterone signalling is membrane receptor (mPR). borne in mind while assessing the validity of PR in The nuclear receptor PR is a transcription regulator. breast cancer management. The PR-mediated Upon ligand binding the principal isoforms PR-A response to progesterone involves Wnt signalling, and PR-B homo- or hetero-dimerize and function as PI3K/Akt/ MAPK signalling; the phenotypic transcription factors. The binding of ligands, agonist outcome is on cell adhesion, proliferation and or antagonist, initiates a conformational change in apoptosis. The ER/PR signalling axis has assumed PR leading to its translocation to the nucleus and much significance in the management of breast binding to PRE of the responsive genes. The cancer patients. However, interpretation of their possibility that PR might function via a non-genomic expression and physiological effects are complicated mode cannot be excluded. by several factors. The cell proliferation/survival The rapidity of some responses to progesterone has results depend upon the ER/PR signalling axis suggested the presence of extranuclear receptor, subject to the provision of which isoform of ER or such as the membrane associated mPRs and PR is functional and the recognition that ER does PGRMC1 (progesterone receptor membrane influence PR function. ERα and ERβ are two ER component 1). The mPRs are GPCRs belonging to isoforms. ERα is pro-proliferation whilst ERβ is the PAQR (progestin and adipoQ receptor) gene inhibitory of cell proliferation. ERα binds to and family (Tang et al, 2005. downregulates PR. The PR-A promoter does contain The mPRs and the PGRMC proteins belonging to a an ERE half site/Sp1 binding site and ER does bind different family are encoded by different genes. It directly to this site (Petz and Nardulli. 2000). Three has been noted that target cells may respond to functionally different PR isoforms of PR, viz. PR-A, progesterone and produce biological effects via the PR-B and PR-C have been identified (reviewed by mPRs and the PGRMC1. This would involve the Kariagina et al. 2008). High PR-A expression has engagement and activation of allied signalling correlated with tumour relapse and with associated systems that culminate in the phenotypic outcome. mutations in the breast cancer susceptibility genes The mPRs function like GPCRs and also directly BRCA1 andBRCA2 (Hopp eet al. 2004; Mote et interacts with progestrone. The physiological al.2004). The differential expression of the isoforms outcome can occur independently of PR. PGRMC1 may be due to methylation (Pathiraja et al. 2011).

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Figure 5: Figure 5 shows the routes of PGR signalling and the crosstalk with the ER signalling pathways and transactivation of EGFR, Wnt/?-catenin ( CTNNB1) possibly influencing cell proliferation. This figures shows an additional mPR route to cell proliferation via PKA/cAMP activating the transcription factors CREB / CREM / ATF-1. The earlier figure has not shown this, but has indicated mPR working through the MAPK/Akt and NO route to cell proliferation and invasion. It ought to be noted here that the activation of the MAPK/ ERK1 ( MAPK3)/ERK2 ( MAPK1) route leads to cell survival and proliferation. The ASK1 ( MAP3K5)/JNK/p38 (signalling is a pro-apoptosis route. There is considerable evidence of crosstalk between the ER/PR axis and the growth factor/PI3K/Akt/mTOR system as shown here. This can effectively explain the downregulation of PR. One has to be mindful also of the possibility that PR may be expressed as splice variants that may not be detected by the antibodies that are currently employed for PR assessment. The PR signalling system may engage in crosstalk with neighbouring genes. The YAP/TAZ of the Hippo system is known to target ER/PR. YAP and WBP2 (WW domain binding protein-2) have been shown to transactivate ER/PR (Dhananjayan et al. 2006). The YAP and ER/PR may be co-ordinately regulated in breast cancer. However, it would be necessary to know whether the changes expression of ER and PR occur of their isoforms uniformly or in a differential fashion before any firm conclusions can be drawn concerning how this co-ordination takes place and what the outcome might be.

The PR-A and PR-B isoforms seem to regulate PI3K/MAPK signalling. Also, the G-protein coupled different sets of target genes. PR-B isoform is receptor GPCR30 has been recognised as a associated with increase in cell migration but not on membrane receptor of oestrogen and the activation cell proliferation or survival. Suppression of PR-B of GPCR30 leads to signalling by the non-genomic inhibits cell migration. Many publications have mode. The oestrogens produce many physiological reported contradictory phenotypic effects of PR effects by activating of GPCRs and driving agonists and antagonists. These are most likely the PI3K/Akt and MAPK/ERK signalling. Oestrogens outcome of the differential signalling by the can also upregulate the expression of MMPs and canonical and the non-canonical receptors, which is promote invasion. Therefore, the overall outcome not often taken into cognisance. The differential would be a result of the balance of activation of the signalling is highlighted in Figure 5 ESR1/PR axis, including the balance of the PR The ER/PR signalling axis displays a complex isoforms. This probably applies also to the circuitry of interaction and inter-regulation. When promotion or inhibition of inflammatory responses. ER is non-functional the hormonal response is Presumably, this is one of the reasons why so much attenuated. When functional, ER can induce the controversy has surrounded the clinical value of PR expression of PR. Equally, PR can regulate ER in breast cancer, which is nonetheless shown to be a function. In breast cancer cells, both oestrogen and significant factor in patient management (reviewed progesterone can activate the Src/Erk pathway. PR by Sherbet, 2011, 2017). Another caveat to be possesses two domains that can interact with the considered is that the ER/PR signalling axis may be ligand-binding domain of ERα and in this way influenced by neighbouring genes such as the YAP1/ mediate the activation of Src signalling (Ballaré et al. TAZ of the Hippo system. 2003). In fact, PR may regulate ER function in breast cancer and possibly also negatively regulate other Mutations oestrogen-activated signalling to suppress cell proliferation (Mohammed et al. 2015). Besides Somatic operating the canonical path of genetic transcription PGR mutations are infrequent in cancers; the by binding to EREs in responsive genes, the ER can frequency is around 1% for all cancers. Mis-sense also function in a non-genomic fashion which does mutations were the most frequent type. The mutation not involve direct genetic regulation. ER can frequency for endometrial cancer, adenocarcinoma influence cell proliferation by the activation of of the stomach, cutaneous melanoma, small cell lung

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cancer (SCLC), and oesophageal carcinoma was post-menopausal women are at greater risk of between 2.6% to 4.4% of samples with PAMs (point developing PR-negative ovarian cancer than a accepted mutations). The frequency of all PGR corresponding group of pre-menopausal women. mutation for breast cancer was 0.52% and for The use of oral contraceptives or HRT did not have ovarian cancer 0.32 (IntOGen; any influence (Shafrir et al. 2016). However, this www.intogen.org/search?gene=PGR). study has not differentiated between PR-B and PR- Among the many polymorphic forms of the PGR A expression. This is an important provision. They gene is the polymorphism called PROGINS. This subscribe to the view that the deregulation of ER has a PV/HS-1 Alu insertion in intron 7 and two signalling could have led to the loss of PR. ERα can point mutations, V660L in exon 4 and H770H in totally suppress PR signalling and in the absence of exon 5. The Alu element has a half ERE/Spl binding ERα, PR-A can inhibit the suppressor effects of PR- site, which enhances the transcription function of B. It is needless to say that the established view is PROGINS in response to oestradiol (Agoulnik et al. that pre-menopausal women run a higher risk of 2004). PROGINS may be associated with enhanced ovarian cancer than post-menopausal women. But risk of ovarian, breast and prostate cancer (Leite et for this generalisation the corresponding information al. 2008; Govindan et al. 2007; Engehausen 2005). on PR status is not currently available. Also, Equally, some studies have denied the link of paradoxically, the situation obtaining in breast PROGINS with cancer risk. cancer is quite the opposite. The use of aromatase Over the past decade several SNPs in the PGR gene inhibitors has no plainly perceived advantage in have been identified; many are inconsequential ones, ER+/PR- breast cancer. Whether the findings have but some have been related to possible links to the any beraring on the use of these inhibitors in ovarian risk of development of breast, endometrial and cancer is debatable. colorectal cancers and endometriosis. The SNPs Purdie et al. (2014) reported that the breast cancer occur in the exons and some in the promoter region molecular subtype luminal A reflects the best of the gene which is thought to have altered the prognosis. Indeed, luminal A consistently shows expression of the receptor. These findings have not high PR expression than luminal B (Prat et al. 2014). enabled substantive conclusions regarding their Caronongan et al. (2016) have analysed ER/PR data significance to the disease process. The presence of derived from both immunohistochemical and ligand SNPs in the ER genes should also be sought whilst binding assays, The IHC-determined PR correlated looking any PGR abnormalities. The perceived more significantly than ER with both nodal status changes in the expression of PGR transcripts or the and 5-year disease-free survival. Also in ligand proteins cannot be assumed to be a direct binding assays, PR correlated better than ER with consequence of the SNPs in PGR genes. The latter survival. A clear differentiation between PR and ER could well be a secondary outcome of alterations in has emerged from this study, with PR displaying ER. greater correlation than ER with disease progression and prognosis. Implicated in Cytogenetics Breast cancer There is very little cytogenetic assessment of the association of PR and ER with chromosomal Prognosis abnormalities and the prevalence of homogeneusly ER and PR are invaluable aids in assessing the staining regions. Efforts were made in this regard growth and progression of breast cancer. These some years ago. Some reports have claimed receptors are important prognostic markers. The correlations of reduced ER and or PR with correct functioning of PR seems to be essential for cytogenetic abnormalities. But no valuable proper growth signalling by ER. In historical information has accrued so far. perspective, the significance of PR is highlighted by A translocation involving Xq24 of the PGRMC1 the finding that ER+/PR+ patients have good locus has been reported to be associated with prognosis and may respond better to hormone reduced expression of PGRMC1 (Mansouri et al. treatment than ER+/PR- patients. Combining ER/PR 2006). expression with cell proliferation markers is The deletion of 11q21 is not infrequent in predictive of nodal involvement and 5-year disease lymphoproliferative disorders and non-Hodgkin's free survival (Osborne, 2005; Andronas et al. 2003). lymphomas. The known translocations involving Furthermore, ER-/PR+ tumours respond to 11q21 do occur at the identified breakpoints endocrine therapy better than ER-/PR- tumours. (Fletcher et al. 1993). Whether these affect 11q22.1 Possibly, PR may produce good clinical outcome is not known. The 11q22-q23.1 region itself does independently of ER. Patients with PR+ disease harbour breakpoints at which translocations and show longer survival (Osborne, 1998; Osborne et al. deletions occur in hematologicval malignancies 2005; Lapidus et al. 1998). A recent report states that including AML and non-Hodgkins lymphoma

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(Tanaka et al.2001). Interestingly, a breakpoint has BRCA1 cancer susceptibility gene. Three of the been established which includes the PGR sequence variants which were associated unfavorably with in 11q22.2-q25 (Ben-Abdallah-Bouhjar et al. 2013). enhanced risk also adversely affected disease-free Ovarian non-Hodgkin's lymphoma can be ER- and survival (Tecza et al. 2015). It would be interesting PR-negative (Johansson et al. (2003), but one should to see such a link exists in breast cancer which has a hasten to add that there is no suggestion that this is familial link with ovarian cancer. due to the loss of or translocation involving the PR At present there is no evidence of an association in locus. cervical neoplasia or uterine fibroids. Mutation at a Genetic recombination, whether in the form of low frequency and some SNPs have been related to translocations or sister chromatid recombination, some gynaecological malignancies and breast cancer tend to occur at fragile sites and these as stated above. recombinations can include growth factor genes and genes linked with tumorigenesis. Sister chromatid To be noted recombination occurs more frequently at the fragile sites. Five fragile sites can be identified in the region Note 11q13 to q23.3, viz. three common fragile sites The use of progesterone antagonists or agonists to FRA11F 11q14.2, FRA11G 11q23.3 and FRA11H control cell proliferation is not a new thought. The 11q13, and two rare folate sensitive fragile site r- effects of agonists such as mifepristone, ORG 31710 FRA11A 11q13.3 and r-FRA11B 11q23.3 and onapristone as single agents or in combination (Debacker and Kooy, 2007). with inhibitors of the interacting ER system were investigated some while ago (Klijn et al. 2000). Prostate cancer However, a most important obstacle to the proper Prognosis assessment the outcomes of many subsequent studies High levels of PR have been claimed to correlate is that one has to have accurate information on the with prostate cancer progression. Differential functional PR and ER isoforms. PRs can act as expression has also been reported in benign prostatic activators or repressors of transcription. PR-A is a hyperplasia and cancer. However, given that ligand ligand dependent repressor of PR-B, mPR and ERβ. activated PR-A can inhibit PR-B effects, it is The prevailing molecular environment is a critical essential to note this differentiation and factor. appropriately check the status of both isoforms to Mifepristone can inhibit cell proliferation, and make a valid conclusion. downregulate VEGFA expression and suppress A link seems to have been established between PR angiogenesis (Elmaci et al. 20016). Combination expression levels and androgen-insensitivity of with angiogenesis inhibitors would be an open prostate cancer. The findings appear to suggest that option. PR could be taking control in the loss of androgen There has been enhanced interest in mifepristone and mediated regulation (Detchokul et al. 2015). It has its metabolite metapristone as therapeutic agents, been suggested this could be due to the similarities given that they can suppress ER and glucocorticoid between the androgen receptor and PR in respect of receptor induced cell proliferation. Mifepristone is their DNA binding domain sequences. also said to influence E-cadherin expression which Ovarian cancer would suggest possible suppression of invasion. This is claimed to be associated with the suppression of Note EMT (Yu et al. 2016). Other adhesion dependent The expression of genetic variant PR isoforms and modes of action have also been implicated. PROGINS has been attributed with alteration of risk These findings vastly strengthen the case for the of developing ovarian cancer. But, equally, this has therapeutic use of the drug. been strongly disputed. There is no overwhelming In a placebo controlled double blind trial disease free evidence that the isoforms or the PROGINS progression was noted over a two year period in a haplotype expression is associated with third of eligible patients with unresectable gynaecological malignancies. Quite paradoxically, meningioma treated with mifepristone (Ji et al. the PROGINS allele has been attributed with 2015). Onaprinstone also inhibits cell proliferation. enhancing ovarian cancer risk while decreasing However, its hepatotoxicity might have muted the breast cancer risk. A similar differentiation has also interest in it. been claimed in respect of the risk of developing PR- Many clinical trials assessing the effects of negative ovarian cancer in post-menopausal women. mifepristone are underway; the outcome is awaited. The status of the BRCA genes could be relevant in The results of trial with ovarian cancer are not this context. An illuminating fact that has emerged encouraging. recently is the association of PR polymorphism in Shapiro et al. (2011) have developed small the presence of PROGINS with ovarian cancer risk molecular inhibitors that reduce the interaction of in a group of patients carrying mutations in the ER and AR with DNA. One inhibitor that they have

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studied in some detail is 8- Cork DM, Lennard TW, Tyson-Capper AJ. Progesterone ((benzylthio)methyl)theophylline (TPBM; 8- receptor (PR) variants exist in breast cancer cells characterised as PR negative Tumour Biol 2012 benzylsulfanylmethyl-1,3-dimethyl-3,7- Dec;33(6):2329-40 dihydropurine-2,6-dione) which decreases ER Debacker K, Kooy RF. Fragile sites and human disease binding to ERE responsive genes. The structurally Hum Mol Genet 2007 Oct 15;16 Spec No related ER inhibitor, p-fluoro-4-(1,2,3,6-tetrahydro- 1,3-dimethyl-2-oxo-6- thionpurin-8- Detchokul S, Elangovan A, Crampin EJ, Davis MJ, Frauman AG. Network analysis of an in vitro model of androgen- ylthio)butyrophenone (TPSF) was markedly more resistance in prostate cancer BMC Cancer 2015 Nov effective It was around 15-fold more potent than the 10;15:883 parent compound. It would be interesting to see the Dhananjayan SC, Ramamoorthy S, Khan OY, et al. WW phenotypic outcome of combination of these domain binding protein-2, an E6-associated protein inhibitors with PR inhibitors. This research group interacting protein, acts as a coactivator of estrogen and has studied the PR inhibitor 6-Thio-8-(2- progesterone receptors Mol Endocrinol 2006 ethylbutyl)thiotheophylline. This is novel in the Oct;20(10):2343-54 sense that it binds outside the PR ligand-binding Elmaci , Altinoz MA, Sav A, Yazici Z, Ozpinar A. Giving pocket (Aninye et al. 2012). Largely. such studies another chance to mifepristone in pharmacotherapy for aggressive meningiomas-A likely synergism with have not strayed beyond in vitro tests. hydroxyurea? Curr Probl Cancer 2016 Sep - Dec;40(5- Over the past few years several new progestins have 6):229-243 doi: 10 surfaced, mainly for use in HRT. They may have Engehausen DG, Endele S, Krause SF, Rith T, Schrott KM, protective effect by opposing cell proliferation Akcetin Z. Polymorphisms in the human progesterone induced by oestrogens. Indeed, it has been claimed receptor (PGR) gene of two human prostate that some progestins may prevent certain forms of adenocarcinoma cell lines Anticancer Res 2005 May- cancer. Jun;25(3A):1607-9 Fletcher JM, Evans K, Baillie D, Byrd P, Hanratty D, Leach References S, Julier C, Gosden JR, Muir W, Porteous DJ, et al. Schizophrenia-associated chromosome 11q21 Agoulnik IU, Tong XW, Fischer DC, Körner K, Atkinson NE, translocation: identification of flanking markers and Edwards DP, Headon DR, Weigel NL, Kieback DG. A development of chromosome 11q fragment hybrids as germline variation in the progesterone receptor gene cloning and mapping resources Am J Hum Genet 1993 increases transcriptional activity and may modify ovarian Mar;52(3):478-90 cancer risk. J Clin Endocrinol Metab. 2004 Govindan S, Ahmad SN, Vedicherla B, et al. Association of Dec;89(12):6340-7 progesterone receptor gene polymorphism (PROGINS) with Ahmed IS, Rohe HJ, Twist KE, Craven RJ. Pgrmc1 endometriosis, uterine fibroids and breast cancer Cancer (progesterone receptor membrane component 1) Biomark 2007;3(2):73-8 associates with epidermal growth factor receptor and Hopp TA, Weiss HL, Hilsenbeck SG, Cui Y, Allred DC, regulates erlotinib sensitivity. J Biol Chem. 2010 Aug Horwitz KB, Fuqua SA. Breast cancer patients with 6;285(32):24775-82 progesterone receptor PR-A-rich tumors have poorer Andronas M, Dlay SS, Sherbet GV. Oestrogen and disease-free survival rates Clin Cancer Res 2004 Apr progesterone receptor expression influences DNA ploidy 15;10(8):2751-60 and the proliferation potential of breast cancer cells. Ji Y, Rankin C, Grunberg S, Sherrod AE, Ahmadi J, Anticancer Res. 2003 May-Jun;23(3C):3029-39 Townsend JJ, Feun LG, Fredericks RK, Russell CA, Aninye IO, Berg KC, Mollo AR, Nordeen SK, Wilson EM, Kabbinavar FF, Stelzer KJ, Schott A, Verschraegen C. Shapiro DJ. 8-alkylthio-6-thio-substituted theophylline Double-Blind Phase III Randomized Trial of the analogues as selective noncompetitive progesterone Antiprogestin Agent Mifepristone in the Treatment of receptor antagonists. Steroids. 2012 May;77(6):596-601 Unresectable Meningioma: SWOG S9005 J Clin Oncol 2015 Dec 1;33(34):4093-8 Ballaré C, Uhrig M, Bechtold T, Sancho E, Di Domenico M, Migliaccio A, Auricchio F, Beato M. Two domains of the Johansson B, Mertens F, Mitelman F. Cytogenetic deletion progesterone receptor interact with the estrogen receptor maps of hematologic neoplasms: circumstantial evidence and are required for progesterone activation of the c-Src/Erk for tumor suppressor loci Genes Chromosomes Cancer pathway in mammalian cells. Mol Cell Biol. 2003 1993 Dec;8(4):205-18 Mar;23(6):1994-2008 Kariagina A, Aupperlee MD, Haslam SZ. Progesterone Ben-Abdallah-Bouhjar I, Mougou-Zerelli S, Hannachi H, receptor isoform functions in normal breast development Ben-Khelifa H, Soyah N, Labalme A, Sanlaville D, Elghezal and breast cancer Crit Rev Eukaryot Gene Expr H, Saad A. Phenotype and micro-array characterization of 2008;18(1):11-33 duplication 11q22.1-q25 and review of the literature. Gene. Klijn JG, Setyono-Han B, Foekens JA. Progesterone 2013 Apr 25;519(1):135-41 antagonists and progesterone receptor modulators in the Caronongan A 3rd, Venturini B, Canuti D, Dlay S, Naguib treatment of breast cancer Steroids 2000 Oct-Nov;65(10- RN, Sherbet GV. Neural Analyses Validate and Emphasize 11):825-30 the Role of Progesterone Receptor in Breast Cancer Lapidus RG, Nass SJ, Davidson NE. The loss of estrogen Progression and Prognosis. Anticancer Res. 2016 and progesterone receptor gene expression in human Apr;36(4):1909-15 breast cancer J Mammary Gland Biol Neoplasia 1998 Jan;3(1):85-94

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Leite DB, Junqueira MG, de Carvalho CV, Massad-Costa Purdie CA, Quinlan P, Jordan LB, Ashfield A, Ogston S, AM, Gonçalves WJ, Nicolau SM, Lopes LA, Baracat EC, da Dewar JA, Thompson AM. Progesterone receptor Silva ID. Progesterone receptor (PROGINS) polymorphism expression is an independent prognostic variable in early and the risk of ovarian cancer Steroids 2008 Jul;73(6):676- breast cancer: a population-based study Br J Cancer 2014 80 Feb 4;110(3):565-72 Li X, O'Malley BW. Unfolding the action of progesterone Scarpin KM, Graham JD, Mote PA, Clarke CL. receptors J Biol Chem 2003 Oct 10;278(41):39261-4 Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear Mansouri MR, Schuster J, Badhai J, Stattin EL, Lösel R, positioning and coregulator expression Nucl Recept Signal Wehling M, Carlsson B, Hovatta O, Karlström PO, 2009 Dec 31;7:e009 Golovleva I, Toniolo D, Bione S, Peluso J, Dahl N. Alterations in the expression, structure and function of Shafrir AL, Rice MS, Gupta M, Terry KL, Rosner BA, Tamimi progesterone receptor membrane component-1 (PGRMC1) RM, Hecht JL, Tworoger SS. The association between in premature ovarian failure Hum Mol Genet 2008 Dec reproductive and hormonal factors and ovarian cancer by 1;17(23):3776-83 estrogen-α and progesterone receptor status Gynecol Oncol 2016 Dec;143(3):628-635 Marshburn PB, Zhang J, Bahrani-Mostafavi Z, Matthews ML, White J, Hurst BS. Variant progesterone receptor Shapiro DJ, Mao C, Cherian MT. Small molecule inhibitors mRNAs are co-expressed with the wild-type progesterone as probes for estrogen and androgen receptor action J Biol receptor mRNA in human endometrium during all phases of Chem 2011 Feb 11;286(6):4043-8 the menstrual cycle Mol Hum Reprod 2005 Nov;11(11):809-15 Sherbet GV. Growth factors and their receptors in cell differentiation, cancer and cancer therapy. Elsevier, 2011. Misrahi M, Venencie PY, Saugier-Veber P, Sar S, Dessen Hardcover ISBN: 9780123878199 . eBook ISBN: P, Milgrom E. Structure of the human progesterone receptor 9780123878205 gene Biochim Biophys Acta 1993 Nov 16;1216(2):289-92 Sherbet GV.. Molecular approach to cancer management. Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Elsevier, 2017 (in press). Tarulli GA, Serandour AA, Birrell SN, Bruna A, Saadi A, Menon S, Hadfield J, Pugh M, Raj GV, Brown GD, D'Santos Springwald A, Lattrich C, Skrzypczak M, Goerse R, C, Robinson JL, Silva G, Launchbury R, Perou CM, Stingl Ortmann O, Treeck O. Identification of novel transcript J, Caldas C, Tilley WD, Carroll JS. Progesterone receptor variants of estrogen receptor α, β and progesterone modulates ERα action in breast cancer Nature 2015 Jul receptor gene in human endometrium Endocrine 2010 16;523(7560):313-7 Jun;37(3):415-24 Mote PA, Leary JA, Avery KA, Sandelin K, Chenevix-Trench Tanaka K, Eguchi M, Eguchi-Ishimae M, Hasegawa A, G, Kirk JA, Clarke CL; kConFab Investigators. Germ-line Ohgami A, Kikuchi M, Kyo T, Asaoku H, Dohy H, Kamada mutations in BRCA1 or BRCA2 in the normal breast are N. Restricted chromosome breakpoint sites on 11q22-q23 1 associated with altered expression of estrogen-responsive and 11q25 in various hematological malignancies without proteins and the predominance of progesterone receptor A MLL/ALL-1 gene rearrangement Cancer Genet Cytogenet Genes Chromosomes Cancer Tang YT, Hu T, Arterburn M, Boyle B, Bright JM, Emtage Nagao K, Kohno N, Wakita K, Hikiji K, Yamamoto S, Hirata PC, Funk WD. PAQR proteins: a novel membrane receptor H, Hisatomi H. Expression of a novel splicing variant family defined by an ancient 7-transmembrane pass motif deleting exons 4 and 6 of the progesterone receptor gene is J Mol Evol 2005 Sep;61(3):372-80 a rare event in breast cancer Oncol Rep 2003 Mar- Tecza K, Pamula-Pilat J, Kolosza Z, Radlak N, Grzybowska Apr;10(2):305-8 E. Genetic polymorphisms and gene-dosage effect in Osborne CK. Steroid hormone receptors in breast cancer ovarian cancer risk and response to paclitaxel/cisplatin management Breast Cancer Res Treat 1998;51(3):227-38 chemotherapy J Exp Clin Cancer Res 2015 Jan 16;34:2 Osborne CK, Schiff R, Arpino G, Lee AS, Hilsenbeck VG. Wardell SE, Kwok SC, Sherman L, Hodges RS, Edwards Endocrine responsiveness: understanding how DP. Regulation of the amino-terminal transcription progesterone receptor can be used to select endocrine activation domain of progesterone receptor by a cofactor- therapy Breast 2005 Dec;14(6):458-65 induced protein folding mechanism Mol Cell Biol 2005 Oct;25(20):8792-808 Pathiraja TN, Shetty PB, Jelinek J, He R, Hartmaier R, Margossian AL, Hilsenbeck SG, Issa JP, Oesterreich S. Yamanaka T, Hirata S, Shoda T, Hoshi K. Progesterone Progesterone receptor isoform-specific promoter receptor mRNA variant containing novel exon insertions methylation: association of PRA promoter methylation with between exon 4 and exon 5 in human uterine endometrium worse outcome in breast cancer patients Clin Cancer Res Endocr J 2002 Aug;49(4):473-82 2011 Jun 15;17(12):4177-86 Yu S, Yan C, Yang X, He S, Liu J, Qin C, Huang C, Lu Y, Petz LN, Nardulli AM. Sp1 binding sites and an estrogen Tian Z, Jia L. Pharmacoproteomic analysis reveals that response element half-site are involved in regulation of the metapristone (RU486 metabolite) intervenes E-cadherin human progesterone receptor A promoter Mol Endocrinol and vimentin to realize cancer metastasis chemoprevention 2000 Jul;14(7):972-85 Sci Rep 2016 Mar 2;6:22388 Prat A, Cheang MC, Martín M, Parker JS, Carrasco E, This article should be referenced as such: Caballero R, Tyldesley S, Gelmon K, Bernard PS, Nielsen TO, Perou CM. Prognostic significance of progesterone Sherbet GV. PGR (progesterone receptor). Atlas Genet receptor-positive tumor cells within immunohistochemically Cytogenet Oncol Haematol. 2017; 21(11):389-397. defined luminal A breast cancer J Clin Oncol 2013 Jan 10;31(2):203-9

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Gene Section Review

WNT10B (wingless-type MMTV integration site family) Alessandro Beghini, Francesca Lazzaroni Department of Health Sciences, University of Milan, via A. Di Rudinò, 8 20142, Milan (Italy); [email protected]; [email protected]

Published in Atlas Database: February 2017 Online updated version : http://AtlasGeneticsOncology.org/Genes/WNT10BID42817ch12q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68996/02-2017-WNT10BID42817ch12q13.pdf DOI: 10.4267/2042/68996 This article is an update of : WNT10B (wingless-type MMTV integration site family). Atlas Genet Cytogenet Oncol Haematol 2017;21(11)

injury. Insight into regenerative processes point to Abstract WNT10B as a candidate potentially linking tissue WNT10B is a member of the WNT ligand gene regeneration and cancer. family encoding a secreted growth factor that has Recently reported evidences support a role of the been reported to have role in a wide range of hematopoietic regeneration-associated WNT10B on biological actions. Wnt10b was originally identified AC133+ cells in human Acute Myeloid Leukemia from mouse embryos and the virgin mammary gland, (AML) via a recurrent rearrangement promoted by a the locus was cloned by retroviral insertional mobile human transposable-WNT10B oncogene (ht- activation, similar to the strategy used to identify WNT10B), as a relevant mechanism for WNT10B other mammary oncogenes. During mammary gland involvement in human cancer. development, Wnt10b seems to play a relevant role Keywords as it is the earliest expressed Wnt ligand. It has been WNT10B, Wnt Signaling Pathway, Leukemia, well established that transgenic expression of Breast Cancer Wnt10b in mouse mammary epithelial cells under the control of the MMTV promoter leads to Identity mammary gland hyperplasia, increased proliferation, and branching. Furthermore, WNT10B has epistatic Other names: SHFM6, STHAg8, WNT12 activity on HMGA2, which is necessary and HGNC (Hugo): WNT10B sufficient for proliferation of triple-negative breast Location: 12q13.2 cancer. The role of Wnt10b in immune system was first described in helper T cells, and its expression in Local order: Minus strand DNA. Start at preB and proB cell lines suggested an involvement 48,965,340 and ends at 48,971,858 bp from pter. in lymphoid development. Furthermore, in CD8 T This gene is clustered with another family member, cells Wnt10b is induced by parathyroid hormone WNT1, in the chromosome 12q13 region. (PTH), suggesting that Wnt10b is playing an important role in T-cell development nad function. DNA/RNA In a different study increased levels of Wnt10b in the Description bone marrow were found in a regenerative model, in which both the stromal cells and HSCs had increased DNA size: 6519 bp, DNA linear. Exon count: 6. This Wnt10b expression in response to gene has 6 transcripts (splice variants), 56 orthologues, 5 paralogues.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 398 WNT10B (wingless-type MMTV integration site family) Beghini A, Lazzaroni F

Transcription receptors that can activate the canonical (Wnt/β- catenin), or non-canonical (Wnt/PCP or Wnt/Ca+) Six transcript variants encoding different isoforms Wnt pathways. In the absence of Wnt ligand or have been found for this gene (font: presence of Wnt antagonists, the axin/adenomatous www.ensembl.org). polyposis coli ( APC)/casein kinase 1 ( WNT10B-001 ENST00000301061.8: mRNA 2274 CSNK1A1)/glycogen synthase kinase 3 (GSK3) bp, protein 389 aa). protein complex binds and phosphorylates β-catenin WNT10B-002 ENST00000203957.5: mRNA 1817 ( CTNNB1) resulting in ubiquitination and bp, protein 173 aa). proteosomal degradation of β-catenin. The pathway WNT10B-003 ENST00000407467.5: mRNA 1802 is activated when a Wnt ligand binds to the bp, protein 191 aa). transmembrane domain receptor of the Frizzled WNT10B-004 ENST00000413630.1: mRNA 623 family (FZD) and its co-receptor low-density bp, protein 132 aa). lipoprotein receptor-related protein 5 or 6 ( LRP5/( WNT10B-005 ENST00000420388.1: mRNA 559 LRP6). Wnt proteins are characterized by an N- bp, protein 102 aa). terminal signal sequence and by palmitoylation on a WNT10B-006 ENST00000475740.1: mRNA 429 conserved cysteine residue, by the protein Porcupine bp, no protein encoded. ( PORCN). Wnt proteins are also characterized by cysteine residues and are glycosylated and lipid Protein modified at two conserved residues, defining the Description hydrophobic profile of proteins. During the ligand WNT10B receptor interaction, Wnt ligands bind to the Hardiman et al., in 1997 isolated and characterized extracellular N-terminal cysteine-rich domain of the fort the first time the gene WNT10B that encodes a Frizzled (FZD) receptor, which is related to the low 389-amino acid protein with 96.6% sequence density lipoprotein receptor-related protein 5 or 6 identity to mouse Wnt10b. They observed the (LRP5/6). Therefore the cytoplasmic protein expression pattern of WNT10B in different adult Dishevelled ( DVL1) is recruited to the receptor tissues with the highest levels found in heart, skeletal complex and then CK1 and GSK3β phosphorylates muscle and in several human cancer cell lines with the cytoplasmic tail of LRP5/6. Then AXIN1, is elevated mRNA levels observed in HeLa (cervical recruited to the receptor complex and assembly of cancer) cell ( Hardiman et al., 1997). the destruction complex is disrupted. Active Dyregulation of WNT10B is implicated in different dephosphorilated β-catenin will accumulate in the human pathologies as split hand/foot malformation cytoplasm to translocate into the nucleus, where it (SHFM) and obesity (Aziz, 2014; VanCamp 2013). initiates transcription by activating T cell Wnt Signaling factor/lymphoid enhancer factor (TCF/ LEF1) Wnt/β-catenin signaling pathway directs cell transcription factors. When β-catenin is bound to the proliferation and cell fate during embryonic destruction complex is phosphorylated on Serine development and adult homeostasis. Moreover, (Ser) 45 by CSNK1A1 (CK1α) which primes β- deregulation of Wnt signaling is tightly linked to catenin for the sequential phosphorylation of human disease, such as multiple forms of cancer and Threonine (Thr) 42, Ser 39, and Ser 37 by GSK3β. bone malformation (Clevers, 2006; Klaus and This phosphorylation of β-catenin promotes the Birchmeier, 2008). Dysregulation of WNT recognition by an E3 ubiquitin ligase, which leads to signalling has been implicated in different types of the ubiquitination and proteasomal degradation of β- cancers, (Lu et al, 2004; Simon et al, 2005; Cadigan catenin. In the absence of β-catenin TCF is linked to and Nusse, 1997; Reya and Clevers, 2005), and the a transcriptional repressor complex with Groucho, a first direct connection between the Wnt pathway and protein which is physically displaced by β- catenin human disease came in the early 1990's. Several (Clevers, 2006; Logan and Nusse, 2004; MacDonald studies pointed out the important role of the Wnt et al., 2009; Mosimann et al., 2009; Staal and signaling in regulating mitotic divisions of Clevers, 2005). Under unstimulated conditions, β- hematopoietic stem cells (HSCs) (Reya et al., 2003). catenins are rapidly turned over by ubiquitination Wnt proteins were originally identified in and degradation by the proteasome pathway. This Drosophila and mice (Nusslein-Volhard and requires phosphorylation of β-catenin by a Wieschaus, 1980; Nusse and Varmus, 1982), which "degradation complex" consisting of APC, Axin, were called Wingless (Wg) and Int1. Cadigan and GSK3, and CK1, followed by binding of BTRC (β - Nusse identified 19 Wnt proteins that are secreted Trcp) (Rubinfeld et al., 1996; Munemitsu et al.; lipid-modified glycosylated signaling molecules, Willert and Jones, 2006). Signals induced by Wnt essential in various developmental processes proteins interrupt the formation of the degradation (Cadigan and Nusse, 1997), acting both on the complex, there by preventing the phosphorylation secreting cell and neighbouring cells and 10 frizzled and destruction of β-catenin.

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WNT10B (wingless-type MMTV integration site family) Beghini A, Lazzaroni F

Expression receptor) inhibits adipocyte differentiation of murine MSCs with Wnt10b/beta-catenin signaling, In human WNT10B is expressed in different tissues suggesting a strong interaction between and organs, including bone marrow, whole blood, Wnt10b/beta-catenin signaling and the the renin- lymph node, thymus, cerebellum, brain, retina, angiotensin system (RAS), and providing important spinal cord, heart, smooth muscle, skeletal muscle, insights into the pathophysiology of obesity and small intestine, colon, adipocyte, kidney, liver, lung, obesity-related consequences (Matsushita et al., pancreas, thyroid, salivary gland, adrenal gland, 2016). skin, ovary, uterus, placenta, cervix and prostate Lei et al., evidenced in 2014 that in response to (http://www.genecards.org/cgi- prolonged ectopic Wnt10b-mediated β-catenin bin/carddisp.pl?gene=WNT10B). activation, regenerating anagen hair follicles grew Aprelikova et al., showed that MIR148A is larger in size. These results were confirmed by downregulated in 94% of cancer-associated Zhang et al., who provided the evidence that Wnt10b fibroblasts (CAFs) compared with matched normal can induce hair follicle regeneration, in a time tissue fibroblasts (NFs) established from patients dependent manner, because a prolonged with endometrial cancer. They revealed that overexpression of Wnt10b induced an abnormal hair WNT10B is a direct target of MIR148A in CAFs follicle regeneration by epidermal keratinocyte from endometrial cancers and demonstrated that its transformation, whereas transient overexpression of upregulation in these cells increases tumor cell Wnt10b induces only hair follicle regeneration. They motility (Aprelikova et al., 2013) found that Wnt10b promoted the proliferation of hair Localisation follicle stem cells from 24 hours after Adenovirus WNT10B is a ligand secreted glycoprotein found vector AdWnt10b injection, and after seventy-two mainly in the extracellular compartment. WNT10B hours from AdWnt10b injection, cells outside of proteins bind to the extracellular N-terminal bulge area began to proliferate, providing the cysteine-rich domain of the Frizzled (FZD) evidence that the overexpression of WNT10B might receptors, which is in a complex with the low density activate the hair follicle stem cells (HFSCs) inducing lipoprotein receptor-related protein 5 or 6 (LRP5/6). hair follicle regeneration (Lei et al., 2014; Zhang et FZD receptors are seven-pass transmembrane al., 2016). receptors which have cycteine-rich domains (CRD) The role of Wnt10b in immune cells was first in their N-terminus. Through the CRD, FZD receptor described in helper T cells (Hardiman et al., 1996), binds Wnt ligands. Wnt10b mRNA has been found during thymic development at embryonic day 13 (E13), and it is Function also found in the adult thymus (Balciunaite et al. It was demonstrated that Wnt10b is expressed in 2002), suggesting that it should play a critical role, cardiomyocytes and stored in the intercalated discs in an intrathymic T-cell development. Furthermore, both in normal human and mouse hearts. Recently, it was demonstrated that in CD8+ T cells Wnt10b is Palk et al., evidenced that after injury, Wnt10b induced by parathyroid hormone (PTH) in an expression is upregulated in cardiomyocytes during osteoporosis model (Terauchi et al. 2009). the granulation tissue formation phase of cardiac Wolf et al, in 2016 examined the interaction between repair, leading an increased angiogenesis by PTH (parathyroid hormone) and WNT10B in induction of KDR (vascular endothelial growth periodontal regeneration, evidencing the interplay of factor receptor 2, Vegfr-2) expression, formation of T cells and human periodontal ligament (hPDL) cells coronary-like vessels surrounded by vascular via the WNT10B pathway as a modulating factor for smooth muscle cells (vSMCs) via induction of the anabolic properties of the hormone in periodontal ANGPT1 (angiopoietin-1) and cardiomyogenesis regeneration. within scar tissue. The authors, highlighetd the role During last years, the research group of Miranda- of Wnt10b in a cardiac repair by arteriole formation Carboni showed that Wnt10b has an important role reducing the fibrosis and stimulating arteriole during the mammary gland development, bacause is formation in NF-KB-dependent manner (Paik et al., expressed at the earliest time during differentiation 2015). of the mammary placode (Veltmaat et al. 2004;), Davis et al., demonstrated that Wnt/beta-catenin suggesting that Wnt10b could be the placode signaling is a major regulator of mesenchymal stem specifier. cells fate (Davis et al., 2008). Matsushita et al., Its specific role remains to be investigated. reported that Wnt10b/beta-catenin signaling is Moreover, Hamamoto et al highlighted that considered to act as a brake for adipogenic SMYD3upregulates WNT10B as a direct differentiation, suggesting an important role of downstream gene and could promote breast Wnt10b as an endogenous regulator of adipogenesis. carcinogenesis by directly regulating expression of In addition, Matsushita et al., in their study the proto-oncogene WNT10B (Hamamoto et al., demonstrated that AGTR2 (angiotensin II type 2 2006).

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WNT10B (wingless-type MMTV integration site family) Beghini A, Lazzaroni F

Recently, Yu et al, in 2016 revealed a heterozygous (WNT10BIVS1) was restricted in a cohort of patients missense mutation (c.632G>A [p.Arg211Gln]) in with intermediate/unfavorable risk AML. It has also WNT10B in all family members affected by been identified at genomic level an intronless oligodontia, a severe form of tooth agenesis, is WNT10B oncogene short form named ht-WNT10B, genetically and phenotypically a heterogeneous and characterized by the 77 IVS1 nucleotides in the condition (Yu et al., 2016). 5'-flanking region, the absence of exons 1 and 4, and Finally, Beghini et al, in 2012 examining the role of the presence of a G/A single nucleotide variation at Wnt signaling in acute myeloid leukemia, provided the exon junction 2-3. The ht-WNT10B suggests its direct evidence of a ligand-dependent activation of involvement in a non-random microhomology- the regeneration-associated Wnt pathway (Congdon mediated recombination generating the rearranged et al, 2008), defining the term "regeneration" as the WNT10BR (Lazzaroni et al., 2016). physiological phenomena of reconstitution from Endometrial Cancer injury requiring rapid expansions of HSCs by reactivation of developmental pathways (Angers and Chen et al., recently demonstrated that the positive Moon, 2009; Bowman, et al., 2012). They revealed expression of WNT10B molecule in cancerous that the ligand-dependent Wnt signaling is induced endometrial tissues, was higher than hyperplastic or in AML through a diffuse expression and release of normal endometrium. They identified that difference WNT10B, a hematopoietic stem cells regenerative- in Wnt10b levels was significant among cancer associated molecule (Beghini et al., 2012). subgroups for histological type, grade of differentiation, and lymphovascular metastasis. Homology During the follow-up, it was demonstrated that The WNT10B gene is conserved in chimpanzee, WNT10B gene expression was frequently Rhesus monkey, dog, cow, mouse, rat, zebrafish, upregulated in Endometrial Cancer (EC) and fruit fly, mosquito, and frog. associated with better prognosis in EC patients, suggesting that WNT10B expression is stage- Implicated in dependent. Collectively, the authors suggested that the up- Acute Myeloid Leukemia regulation of WNT10B may contribute to Recently, Beghini et al., evidenced that the Endometrial Cancer with favorable prognosis, regenerative function of WNT signaling pathway is characterized by high-grade, advanced-stage and no defined by the up-regulation of WNT10B, lymph node metastasis (Chen et al., 2012). WNT10A, WNT2B and WNT6 loci, revealing that Prostate Cancer the ligand-dependent Wnt signaling is induced in Acute Myeloid Leukemia patients, through a diffuse Recently it was revealed that WNT10B molecule is expression and release of WNT10B, a hematopoietic upregulated in prostate cancer reactive stroma and it stem cells regenerative-associated molecule. is expressed in the prostate stromal cell lines, by WNT10B was identified as a major locus associated decreasing apoptosis in LNCaP cancer cells and with the regenerative function and over-expressed in increasing angiogenesis. The authors identified an bone marrow sections of all AML patients. The Wnt autocrine stimulation of expression of stem cell signaling activation signature represented by associated genes as BDNF that enhances VEGFA accumulation of the active form of dephosphorylated expression in an autocrine manner. These findings beta-catenin (ABC), is shared by only the suggested the WNT10B role in regulating expression subpulation of AC133bright AML cells (8-10 μm of genes associated with mesenchymal stem cell diameter of the nuclei), likely induced through an biology in prostate stroma as it does in bone and autocrine/paracrine mechanism. Using the mRNA in adipose tissue (Dakhova et al., 2014). situ detection, a new molecular tool for the mRNA Breast cancer molecules detection directly in situ, they evidenced Bui et al., in 1997 have isolated as the first time, a the constitutive activation of WNT10B transcription WNT gene which has not previously been described in the Bone Marrow (BM) sections derived from in human, a human homologue of mouse Wnt10b AML patients, suggesting that the regenerative (Bui et al., 1997). According to their research, the WNT signaling is a stem cell-associated function high WNT10B mRNA expression in different breast altered in AML stem cell fraction (Beghini et al., cell lines, was strictly related to mammary gland 2012). development and disease. Following this point of By the molecular evaluation of the WNT10B locus, view, Lane et al., provided the evidence that it was identified the presence of a recurrent overexpression of WNT10B leads the branching of R rearrangement that generate the WNT10B allele, mammary ducts and the alveolar development. 1 within intron 1 (IVS ) and flanked at the 5' by an Indeed, Veltmaat et al., in 2004 evidenced that unknown non-human sequences (Lazzaroni et al., Wnt10b expression is the earliest fundamental 2016). The expression of the transcript variant ectodermal event (E11.25) defining the mammary

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Nüsslein-Volhard C, Wieschaus E. Mutations affecting Terauchi M, Li JY, Bedi B, Baek KH, Tawfeek H, Galley S, segment number and polarity in Drosophila. Nature. 1980 Gilbert L, Nanes MS, Zayzafoon M, Guldberg R, Lamar DL, Oct 30;287(5785):795-801 Singer MA, Lane TF, Kronenberg HM, Weitzmann MN, Pacifici R. T lymphocytes amplify the anabolic activity of Nusse R, Varmus HE. Many tumors induced by the mouse parathyroid hormone through Wnt10b signaling. Cell Metab. mammary tumor virus contain a provirus integrated in the 2009 Sep;10(3):229-40 same region of the host genome. Cell. 1982 Nov;31(1):99- 109 Van Camp JK, Zegers D, Verhulst SL, Van Hoorenbeeck K, Massa G, Verrijken A, Desager KN, Van Gaal LF, Van Hul Paik DT, Rai M, Ryzhov S, Sanders LN, Aisagbonhi O, W, Beckers S. Mutation analysis of WNT10B in obese Funke MJ, Feoktistov I, Hatzopoulos AK. Wnt10b Gain-of- children, adolescents and adults. Endocrine. 2013 Function Improves Cardiac Repair by Arteriole Formation Aug;44(1):107-13 and Attenuation of Fibrosis. Circ Res. 2015 Oct 9;117(9):804-16 Veltmaat JM, Van Veelen W, Thiery JP, Bellusci S. Identification of the mammary line in mouse by Wnt10b Peluso S, Chiappetta G. High-Mobility Group A (HMGA) expression. Dev Dyn. 2004 Feb;229(2):349-56 Proteins and Breast Cancer. Breast Care (Basel). 2010;5(2):81-85 Wend P, Wend K, Krum SA, Miranda-Carboni GA. The role of WNT10B in physiology and disease. Acta Physiol (Oxf). Reya T, Clevers H. Wnt signalling in stem cells and cancer. 2012 Jan;204(1):34-51 Nature. 2005 Apr 14;434(7035):843-50 Willert K, Jones KA. Wnt signaling: is the party in the Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert nucleus? Genes Dev. 2006 Jun 1;20(11):1394-404 K, Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003 Yu P, Yang W, Han D, Wang X, Guo S, Li J, Li F, Zhang X, May 22;423(6938):409-14 Wong SW, Bai B, Liu Y, Du J, Sun ZS, Shi S, Feng H, Cai T. Mutations in WNT10B Are Identified in Individuals with Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis Oligodontia. Am J Hum Genet. 2016 Jul 7;99(1):195-201 P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996 May Zhang Y, Xing Y, Guo H, Ma X, Li Y. Immunohistochemical 17;272(5264):1023-6 study of hair follicle stem cells in regenerated hair follicles induced by Wnt10b. Int J Med Sci. 2016;13(10):765-771 Simon M, Grandage VL, Linch DC, Khwaja A. Constitutive activation of the Wnt/beta-catenin signalling pathway in This article should be referenced as such: acute myeloid leukaemia. Oncogene. 2005 Mar Beghini A, Lazzaroni F. WNT10B (wingless-type MMTV integration site family). Atlas Genet Cytogenet Oncol 31;24(14):2410-20 Haematol. 2017; 21(11):398-403. Staal FJ, Clevers HC. WNT signalling and haematopoiesis: a WNT-WNT situation. Nat Rev Immunol. 2005 Jan;5(1):21- 30

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Acute myeloid leukemia with myelodysplasia related changes Alexandra Nagy, Andreas Neubauer Howard Hughes Medical Institute and the Department Pathology, Beckman Center for Molecular and Genetic Medicine, Stanford University, Stanford, California 94305, USA; [email protected] (A Na); Dept. Internal Medicine and Hematology, Oncology and Immunology, Philipps University Marburg,Germany; [email protected] (A Ne)

Published in Atlas Database: January 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/AMLwithmyelodysplID2041.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68997/01-2017-AMLwithmyelodysplID2041.pdf DOI: 10.4267/2042/68997 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

criteria: Abstract - history of myelodysplastic syndrome (MDS) or Acute myeloid leukemia (AML) is a heterogeneous myelodysplastic/myeloproliferative neoplasm clonal disorder with two prominent features: i) (MDS/MPN) hematopoietic progenitor cells loose the ability to - MDS-related cytogenetic abnormalities or differentiate normally and ii) the transformed multilineage dysplasia (≥ 50% dysplastic cells in≥ leukemia cells show an impaired regulation of two hematopoietic lineages) (Arber et al., 2016a). myeloid proliferation. Etiology AML with myelodysplasia-related changes is a sub- entity of AML that has a poor prognosis. It is There are various risk factors which can cause AML characterized by a history of MDS, significant in general. These risk factors can be categorized as morphologic dysplasia, or MDS-related cytogenetic genetic disorders, physical and chemical exposure, features such as -7/del(7q) and others. Whereas the radiation therapy and chemotherapy. Even though prognosis of AML is quite different with respect to many people are exposed, to various degrees, to genetic aberrations, the therapy - except of acute carcinogens, only a few cases may present with a promyelocytic leukemia (APL) - is still relatively known history of carcinogen exposure. Currently, it unchanged from 30 years ago. Therefore, new is not fully understood why some people develop treatment strategies are needed. AML and some do not (Estey and Döhner, 2006). Genetically, many researchers favor the "two-hit" Keywords hypothesis first proposed by Hartmut Beug (Beug et Acute myeloid leukemia, multilineage dysplasia, al., 1978), and later by Gary Gilliland. This myelodysplasia related changes hypothesis states that for transformation, a mutation in a kinase coding gene such as RAS, KIT or FLT3 Clinics and pathology has to occur together with a class II mutation targeting a transcription of nuclear factor such as Disease NPM1, RUNX1 or CEBPA. Today, we know about Acute myeloid leukemia with myelodysplasia a high variation of somatic mutations and related changes (AML-MRC) is a subgroup of AML. chromosomal abnormalities characterizing different It was introduced in 2008 by the WHO classification types of AML. AML-MRC is often associated with and updated in 2016 (Weinberg et al., 2015). A the following chromosomal abnormalities (Table 1) diagnosis of AML-MRC requires ≥ 20% blasts and (Deschler et al., 2006; Weinberg et al., 2015). additionally one of the following three

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Epidemiology transplantation (HSCT) must be considered (Kumar, 2011). As AML-MRC frequently fulfills the high- If the WHO classification is strictly applied, 48% of risk criteria such as: 3(q21q26) abnormalities, all adult AML cases meet the AML-MRC criteria. It RPN1/MECOM (EVI1), del(5q), del(7q), t(6;9), tends to affect more male and is a disease of the other 11q23 abnormalities, 17p abnormalities, or elderly with a median age of 68 years. Additionally, complex aberrant karyotypes described as at least 3 it is associated with a higher frequency of unrelated abnormalities excluding cases with t(8;21), unfavorable cytogenetics and, consequently, a worse inv(16), and t(15;17), an allogeneic stem cell clinical outcome (Davis et al.,2013; Xu et al., 2014; transplantation will be the post-induction therapy of Weinberg et al., 2009). AML-MRC occurs more first choice in most adults (Vardiman and Reichard, often de novo then secondary to myelodysplasia 2015). (Vardiman and Reichard, 2015). Cytology Prognosis The myelodysplastic changes and MDS associated AML-MRC cases commonly present with chromosomal abnormalities of AML-MRC are multilineage dysplasia. This is validated best with associated with a worse prognosis and lower rates of peripheral blood smears or bone marrow smears for event-free survival and overall survival. However, it identifying myeloid and erythroid dysplasia and was shown that there is no difference in prognosis bone marrow biopsy for identifying megakaryocytic between patients with AML-MRC with a history of dysplasia (Falini et al., 2016). Following the WHO MDS and the remaining cases of AML-MRC classification an AML-MRC presents with ≥ 50 % (Weinberg et al., 2009; Arber et al., 2003). Besides, dysplastic cells in at least two hematopoietic AML-MRC with the absence of cytogenetic lineages. The dysplastic features are not unique for abnormalities seem to have a better prognosis AML-MRC, but can be also detected in other (Weinberg et al., 2009). Additionally, AML-MRC hematopoietic diseases, such as MDS (Wu et al., with NPM1 mutations and with or without 2013). Dysplastic neutrophils may exhibit a nucleus- cytogenetic abnormalities show a better prognosis cytoplasm dysynchrony, hypogranulation and (Haferlach et al., 2009). This was also shown for abnormal nuclear segmentation (pseudo-Pelger- CEBPA mutations (Vardiman and Reichard, 2015). Huët anomaly), e.g. bi-nucleated segments Therefore AML-MRC with NPM1 or CEBPA (Weinberg et al., 2015). As mentioned, mutations are excluded from the AML-MRC dyserythropoesis and dysmegakaryopoesis are also category in the WHO classification 2016 (Arber et commonly seen. Dyserythropoesis presents with odd al., 2016). The prognosis of AML-MRC particularly erythroid precusors and sometimes ring sideroblasts, in context of multilineage dysplasia remains as well as multinuclearity, megaloblastoid changes controversial (Vardiman and Reichard, 2015). In and karyorrhexis. Dysmegakaryopoesis commonly patients who have undergone allogenic HSCT there shows hypolobulated micromegakaryocytes, non- is no prognostic difference in AML-MRC patients lobulated nuclei in megakaryocytes of all sizes and compared to AML not otherwise specified (AML- multiple widely separated nuclei (Wakui et al., NOS) (Ikegawa et al., 2016). 2008). Treatment Cytogenetics The therapy of AML-MRC is based on regular AML-therapy with a risk-adapted chemotherapy Cytogenetics morphological including induction chemotherapy ("7+3"; Following the WHO classification, cases of AML daunorubicine plus cytarabine) and postinduction with MDS-related cytogenetic abnormalities meet therapy, such as high-dose cytarabine or in high-risk the criteria of AML-MRC. MDS and AML-MRC patients, allogeneic transplantation in first remission. may show complex karyotype and with Using regular assessments, lab studies including predominantly unbalanced chromosomal cytogenetics and molecular analyses, the patient can abnormalities (Vardiman and Reichard, 2015; be assigned to a risk group and treatment and Miesner et al., 2010). A complex karyotype is prognosis can be determined and the decision defined as three or more unrelated chromosomal between curative chemotherapy/allogeneic stem cell abnormalities and is differentiated into unbalanced transplantation, palliative chemotherapy and best and balanced chromosomal abnormalities (see supportive care can be made (Estey and Döhner, Figure 1). A complex karyotype can lead to aberrant 2006). Chemotherapy can be separated into two expression pattern of regulating genes and is often main parts. First, the induction therapy with the associated with a poor prognosis. Likewise, it is attempt to reach complete remission. Second, the assumed that autosomal monosomy (2 or more consolidation therapy to prolong the complete autosomal monosomies or 1 autosomal monosomy remission. If the patient displays characteristics of plus one or more other chromosomal abnormalities) high risk AML, a hematopoietic stem cell is associated with a poor prognosis.

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Figure 1. Karyotype analysis with MDS related cytogenetic abnormalities: 46,XX,t(4;6)(q21;23),del(5)(q11.2q35),del(7)(q11.2q36),+8,add(11)(p15),del(12)(p12p13),-17. Commonly seen in MDS is the deletion of 5 and 7 (stars) and/or monosomy 17 (cross) (Miesner et al., 2010).

The most common monosomies in AML and MDS outcome. The same is true for trisomy 8, del(20q) are monosomies 5 and 7 which are known for its and loss of chromosome Y (Pabst et al., 2009; Wu et poor prognosis (Takahashi, 2011; Cazzola et al., al., 2013). 2013). Table 1 shows the commonly occurring Gene Effect balanced and unbalanced chromosomal arrangement abnormalities. activation of the platelet- >3 unrelated abnormalities, none 5q33 derived growth factor- β ( Complex of which are included in the PDGFRB ) Karyotype AML with recurrent genetic 3q26 (MECOM Impaired EVI1 expression abnormalities subgroup (EVI1) locus) (poor prognosis) -7/del(7q) 3q21 (GATA2 Impaired EVI1 expression -5/del(5q) locus) (poor prognosis) i(17q)/t(17p) Unbalanced -13/del(13q) 11q23 (KMT2A Clonal evolution and disease abnormalities del(11q) (MLL) locus) progression in acute leukemia del(12p)/t(12p) t(3;5) fusion product NPM1 / MLF1 idic(X)(q13) Table 2. Common gene arrangements in AML-MRC t(11;16)(q23;p13.3) (Vardiman and Reichard, 2015; Arber et al., 2003; Heldin t(3;21)(q26.2;q22.1) and Lennartsson, 2013; Zuo et al., 2016; Lim et al., 2010) t(2;11)(p21;q23) t(1;3)(p36.3;q21.1) Genes involved and Balanced t(5;12)(q33;p12) abnormalities proteins t(5;7)(q33;q11.2) t(5;17)(q33;p13) As mentioned in Prognosis, the NPM1 mutation can t(5;10)(q33;q21) present with multilineage dysplasia and is associated t(3;5)(q25;q34) with a better outcome. However, there are no genetic somatic mutations fully specific for AML-MRC. As Table 1. Cytogenetic abnormalities for AML with myelodysplasia-related features (modified from Vardiman the subcategory AML-MRC represents almost 50% and Reichard et al. 2015). of all AML cases there can be found all common Common gene arrangements and their effects are somatic mutations of AML concomitantly. In case of displayed in Table 2. According to the 2016 WHO an AML-MRC with a history of MDS commonly classification the MDS related cytogenetic mutated genes in MDS should also be considered, abnormality del(9q) is no longer considered a AML- e.g. SF3B1 which is associated with the formation of MRC defining abnormality. Since del(9q) ring sideroblasts in MDS (Malcovati et al., 2014). commonly occurs together with NPM1 or bi-allelic Somatic mutations have prognostic value and are CEBPA mutations it is also associated with a better assumed to play a critical role in leukemogenesis.

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They can affect signal transduction, DNA Deschler B, Lübbert M. Acute myeloid leukemia: methylation, chromatin modification, transcriptional epidemiology and etiology. Cancer. 2006 Nov 1;107(9):2099-107 regulation, RNA splicing and cohesion- complexes. The most commonly mutated genes in AML are Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006 FLT3, NPM1, CEBPA besides many more (Cancer Nov 25;368(9550):1894-907 and Atlas, 2013; Malcovati et al., 2014). Following Falini B, Macijewski K, Weiss T, Bacher U, Schnittger S, the 2016 WHO classification an AML-MRC with Kern W, Kohlmann A, Klein HU, Vignetti M, Piciocchi A, Fazi P, Martelli MP, Vitale A, Pileri S, Miesner M, Santucci A, presence of NPM1 and bi-allelic CEBPA mutation is Haferlach C, Mandelli F, Haferlach T. 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Cancer Genet Cytogenet. 2010 Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Jun;199(2):101-9 Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst Malcovati L, Papaemmanuil E, Ambaglio I, Elena C, Gallì A, C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra Della Porta MG, Travaglino E, Pietra D, Pascutto C, Ubezio MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, M, Bono E, Da Vià MC, Brisci A, Bruno F, Cremonesi L, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen Ferrari M, Boveri E, Invernizzi R, Campbell PJ, Cazzola M. N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez Driver somatic mutations identify distinct disease entities C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, within myeloid neoplasms with myelodysplasia. Blood. 2014 Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Aug 28;124(9):1513-21 Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Miesner M, Haferlach C, Bacher U, Weiss T, Macijewski K, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Kohlmann A, Klein HU, Dugas M, Kern W, Schnittger S, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G. Genomic Haferlach T. Multilineage dysplasia (MLD) in acute myeloid and epigenomic landscapes of adult de novo acute myeloid leukemia (AML) correlates with MDS-related cytogenetic leukemia. N Engl J Med. 2013 May 30;368(22):2059-74 abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: a comparison of Cazzola M, Della Porta MG, Malcovati L. The genetic basis 408 cases classified as "AML not otherwise specified" of myelodysplasia and its clinical relevance. 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with favourable prognosis. Br J Cancer. 2009 Apr JD, Gotlib J, Zehnder JL, Arber DA. Clinical characterization 21;100(8):1343-6 of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system. Takahashi S. Current findings for recurring mutations in Blood. 2009 Feb 26;113(9):1906-8 acute myeloid leukemia. J Hematol Oncol. 2011 Sep 14;4:36 Wu H, Bian S, Chu J, Zhong X, Sun H, Zhang B, Lu Z. Characteristics of the four subtypes of van Dongen JJ, Lhermitte L, Böttcher S, Almeida J, van der myelodysplastic/myeloproliferative neoplasms. Exp Ther Velden VH, Flores-Montero J, Rawstron A, Asnafi V, Med. 2013 May;5(5):1332-1338 Lécrevisse Q, Lucio P, Mejstrikova E, Szczepański T, Kalina T, de Tute R, Brüggemann M, Sedek L, Cullen M, Langerak Xu XQ, Wang JM, Gao L, Qiu HY, Chen L, Jia L, Hu XX, AW, Mendonça A, Macintyre E, Martin-Ayuso M, Hrusak O, Yang JM, Ni X, Chen J, Lü SQ, Zhang WP, Song XM. Vidriales MB, Orfao A. EuroFlow antibody panels for Characteristics of acute myeloid leukemia with standardized n-dimensional flow cytometric myelodysplasia-related changes: A retrospective analysis in immunophenotyping of normal, reactive and malignant a cohort of Chinese patients. Am J Hematol. 2014 leukocytes. Leukemia. 2012 Sep;26(9):1908-75 Sep;89(9):874-81 Vardiman J, Reichard K. Acute Myeloid Leukemia With Zuo W, Wang SA, DiNardo C, Yabe M, Li S, Medeiros LJ, Myelodysplasia-Related Changes. Am J Clin Pathol. 2015 Tang G. Acute leukaemia and myelodysplastic syndromes Jul;144(1):29-43 with chromosomal rearrangement involving 11q23 locus, but not MLL gene. J Clin Pathol. 2017 Mar;70(3):244-249 Weinberg OK, Hasserjian RP, Li B, Pozdnyakova O. Assessment of myeloid and monocytic dysplasia by flow This article should be referenced as such: cytometry in de novo AML helps define an AML with myelodysplasia-related changes category. J Clin Pathol. Nagy A, Neubauer A. Acute myeloid leukemia with 2017 Feb;70(2):109-115 myelodysplasia related changes. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11):404-408. Weinberg OK, Seetharam M, Ren L, Seo K, Ma L, Merker

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Leukaemia Section Short Communication dic(9;12)(p13;p13) PAX5/ETV6 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France; [email protected]

Published in Atlas Database: January 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic0912ID1065.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68998/01-2017-dic0912ID1065.pdf DOI: 10.4267/2042/68998 This article is an update of : dic(9;12)(p13;p13) PAX5/ETV6. Atlas Genet Cytogenet Oncol Haematol 2017;21(11) Strehl S. dic(9;12)(p13;p13) PAX5/ETV6. Atlas Genet Cytogenet Oncol Haematol 2004;8(2) Huret JL. dic(9;12)(p13;p13). Atlas Genet Cytogenet Oncol Haematol 2003;7(3) Huret JL. dic(9;12)(p11-13;p11-12). Atlas Genet Cytogenet Oncol Haematol 1997;1(1)

lymphoblastic leukaemias (BCP-ALL), 2 in chronic Abstract myelogenous leukemia (CML) in blast crisis (BC- Review on dic(9;12)(p13;p13) PAX5/ETV6, with CML), 1 in T-ALL, 1 in CLL, and 1 in NHL not data on clinics and the genes involved. otherwise specified. Keywords Phenotype/cell stem origin Chromosome 9; chromosome 12; Acute ALLs with dic(9;12) are most often L1/L2 and lymphoblastic leukemia; PAX5; ETV6. CD10+, at times CIg+ ALL. Identity Epidemiology The fusion of PAX5 and ETV6 in the The PAX5 gene is altered by mutations, deletions or dic(9;12)(p13;p13) was first described by Strehl et translocations in 30% of BCP-ALL patients and al., 2003. PAX5/ETV6 fusion was found in 18/19 PAX5 chromosomal translocations account for 2-3% (95%) dic(9;12) cases in a study by An et al., 2008, of cases (Cazzaniga et al., 2015). and one case was a dic(9;12)(p13;p12) with a Dic (9;12) represents 1% of pediatric ALL (Behrendt PAX5/SLCO1B3 fusion. et al., 1995) Plotting 32 cases of B-ALL cases reviewed in Clinics and pathology Behrendt et al., 1995 and the 36 cases published by An et al., 2008 (excluding the PAX5/ SLCO1B3 Disease case), median age was 12 years (range:1 yrs - 47 yrs; dic(9;12)(p13;p13) is most often found in B cell no infant case (< 1yr); 5 cases ≤ 2 yrs; 22 cases acute lymphocytic leukemia (B-ALL), and very between ages 2 and 10; 14 cases above 18 yrs); 72% rarely in T-cell acute leukemia (T-ALL), chronic were male patients (sex ratio: 49M/19F). lymphocytic leukemia (CLL), or non Hodgkin Clinics lymphoma (NHL). Of 36 cases of dic(9;12) reviewed in Behrendt et al., Moderate organomegaly. Blood data: moderate 1995, 31 were found in precursor acute WBC.

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dic(9;12)(p13;p13) Top row: G- banding - Courtesy Jean-Luc Lai (left) and Diane H. Norback, Eric B. Johnson, Sara Morrison- Delap UW Cytogenetic Services (middle left and middle); R- banding (right) with chr 12 up side down - Jean Loup Huret; Middle row: G- banding - Courtesy Jacqueline Van Den Akker (left) and Marilyn Slovak (middle left and middle); R- banding (right) with chromosome 12 up side down - Jacqueline Van Den Akker (middle right) and Jean Loup Huret (right); Bottom row: diagram and C-banding - Jean Loup Huret.

Age at diagnosis in 32 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995).

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White blood count, platelets count and Haemoglobin in 32 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995).

Survival in 30 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995). One patient died at day 11 after diagnosis from cerebral hemorrhage during induction treatment (Huret et al., 1990); all other patients were alive and well at the times of publications.

Treatment Bone marrow transplantation is not indicated, nor are Cytogenetics high risk protocols in this leukemia with a fair Note prognosis. The dicentric is formed with loss of parts of 9p and Prognosis 12p; therefore the ploidy is 45 chromosomes in cases Complete remission is obtained in all cases; 5 years where the dic(9;12) is the sole abnormality. survival > 95%.

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Cytogenetics morphological ETV6 (ets variant 6) Of 68 cases (Behrendt et al., 1995; An et al., 2008) Location the dic(9;12) was the sole abnormality (at least 12p13.2 within a sub-clone) in 28 cases (41%), and was accompanied with +8 (19 cases, 28%), +21 (4 cases), DNA/RNA del(6q) (3 cases), or -5/del(5q) (2 cases). Alternative transcripts. Protein Genes involved and Contains a HLH domain, also referred to as the pointed or sterile alpha motif domain, responsible for proteins hetero- and homodimerization, and a ETS-DNA PAX5/ETV6 fusion gene implicates two binding domain, responsible for sequence specific transcription factors, fundamental in hematopoiesis DNA-binding and protein-protein interaction; ETV6 and in B cell development. is an ETS-related transcription factor, transcriptional repressor that binds to DNA sequence 5'- PAX5 (paired box gene 5) CCGGAAGT-3', It can form homodimers or Location heterodimers with ETV7 or FLI1. 9p13.2 DNA/RNA Result of the chromosomal The PAX5 coding region extends over a genomic anomaly interval of approximately 200kb and comprises 10 exons. Two alternative transcripts have been Hybrid gene identified, originating from alternative promotor usage, containing exon 1A or 1B. Full length mRNA Description is 3650 bp. In a study of dic(7;9) (n= 13), dic(9;12) (n=38), and dic(9;20) (n=59), breakpoints on 9p were found to be Protein heterogeneous; however, all breakpoints resulted in PAX5 belongs to the paired box family of loss of a large number of genes on 9p, including the transcription factors, involved in a multitude of tumor suppressor gene, CDKN2A (An et al., 2008). developmental processes. PAX5 was originally 5'PAX5 / 3'ETV6 transcript, no reciprocal transcript identified as a B-cell specific transcription factor (B- due to deletion cell-specific activator protein, BSAP). Recently, it In the dic(9;12) cases, the breakpoints were located has been shown that PAX5 expression is not only within intron 4 of PAX5 in 8 of 8 cases, whereas 7 continuously required for B cell lineage commitment were intron 2 and 1 in intron 1 of ETV6 (An et al., during early B cell development but also for B 2008). lineage maintenance. Contains a paired box (DNA binding) domain, a truncated homeo domain Detection homology region, a transactivation domain, and an RT-PCR, FISH. inhibitory domain. Fusion protein Description

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The PAX5/ETV6 chimeric transcript results in Cazzaniga V, Bugarin C, Bardini M, Giordan M, te Kronnie fusion of the paired box domain (PRD) of PAX5 G, Basso G, Biondi A, Fazio G, Cazzaniga G. LCK overexpression drives STAT5 oncogenic signaling in PAX5 (DNA binding domain of PAX5) to the helix-loop- translocated BCP-ALL patients. Oncotarget. 2015 Jan helix and ETS-binding domains of ETV6 (DNA 30;6(3):1569-81 binding, dimerization and transcription regulation An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman domains of ETV6). AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Of note: the putative chimeric protein contains the Harrison CJ, Irving JA, Strefford JC. Variable breakpoints DNA-binding domains of both fusion partners, target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. namely the PRD and the ETS-domain. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4 Expression / Localisation Behrendt H, Charrin C, Gibbons B, Harrison CJ, Hawkins PAX5/ETV6 localizes in the nucleus and the JM, Heerema NA, Horschler-Bötel B, Huret JL, Laï JL, cytoplasm. Lampert F. Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a Oncogenesis dic(9;12) study group. Leukemia. 1995 Jan;9(1):102-6 PAX5/ETV6 acts as a transcriptional repressor. Cazzaniga G, Daniotti M, Tosi S, Giudici G, Aloisi A, PAX5/ETV6 can multimerize and bind the PAX5- Pogliani E, Kearney L, Biondi A. The paired box domain consensus sequence, determining a dominant gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic negative activity on wild type PAX5. PAX5/ETV6 leukemia case. Cancer Res. 2001 Jun 15;61(12):4666-70 represses 56% and activates 44% of PAX5-target Fazio G, Cazzaniga V, Palmi C, Galbiati M, Giordan M, te genes, respectively in the study by Fazio et al., 2013. Kronnie G, Rolink A, Biondi A, Cazzaniga G. PAX5/ETV6 On the other hand, only a few ETV6 transcriptional alters the gene expression profile of precursor B cells with target genes were differentially expressed. opposite dominant effect on endogenous PAX5. Leukemia. 2013 Apr;27(4):992-5 PAX5/ETV6 determines a PAX5 haploinsufficiency setting; the PAX5/ETV6 fusion protein Fortschegger K, Anderl S, Denk D, Strehl S. Functional heterogeneity of PAX5 chimeras reveals insight for could be actively responsible for the B-cell leukemia development. Mol Cancer Res. 2014 development block, mediated by the repression of Apr;12(4):595-606 physiological PAX5-activated genes (Fazio et al., Huret JL, Heerema NA, Brizard A, Provisor AJ, Benz- 2013). Lemoine E, Guilhot F, Savage JR, Tanzer J. Two additional PAX5-ETV6 also interacted with wild-type ETV6, cases of t dic(9:12) in acute lymphocytic leukemia (ALL): supporting the notion that the ETV6 sterile alpha prognosis in ALL with dic(9:12). Leukemia. 1990 domain mediates oligomerization of ETV6 and Jun;4(6):423-5 ETV6 fusion proteins (Fortschegger et al., 2014). Mahmoud H, Carroll AJ, Behm F, Raimondi SC, Schuster J, LCK is up-regulated by PAX5/ETV6. LCK hyper- Borowitz M, Land V, Pullen DJ, Vietti TJ, Crist W. The non- activation, and down-regulation of its negative random dic(9;12) translocation in acute lymphoblastic leukemia is associated with B-progenitor phenotype and an regulator CSK, lead to STAT5 over-phosphorylation excellent prognosis. Leukemia. 1992 Jul;6(7):703-7 and hyper-activation and to up-regulation of the Strehl S, König M, Dworzak MN, Kalwak K, Haas OA. downstream effectors, MYC and CCND2. PAX5/ETV6 fusion defines cytogenetic entity Hyper-activation of STAT5 pathway can represent a dic(9;12)(p13;p13). Leukemia. 2003 Jun;17(6):1121-3 survival signal in PAX5 translocated cells (Cazzaniga et al., 2015). This article should be referenced as such: Huret JL. dic(9;12)(p13;p13) PAX5/ETV6. Atlas Genet References Cytogenet Oncol Haematol. 2017; 21(11):409-413.

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Leukaemia Section Short Communication i(7)(q10) Anwar N Mohamed Cytogenetics laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA [email protected] Published in Atlas Database: January 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/i7q10ID1077.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68999/01-2017-i7q10ID1077.pdf DOI: 10.4267/2042/68999 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Note Shwachman-Diamond syndrome (SDS) is an Isochromosome 7q, i(7)(q10), is a rare recurrent autosomal recessive disorder, characterized by aberration found in various hematological exocrine pancreatic insufficiency, skeletal neoplasms. In Mitelman's data base, i(7q) is the sixth abnormalities and bone marrow dysfunction. most common isochromosome after i(17q), i(8q), The disease manifests with neutropenia, but anemia, i(1q), i(12p), and i(6p) in human neoplasms. The thrombocytopenia, or aplastic anemia may as well incidence of this abnormality, and genes involved occur. SDS patients have a high risk to develop are presented in this review. myelodysplastic syndrome and/or acute myeloid Keywords leukemia (MDS/AML). Chromosome 7; isochromosome; Hepatosplenic T- The frequency of leukemia in patients with this cell lymphoma; Shwachman Diamond syndrome; syndrome is as much as 36% by age 30 years and Acute lymphoblastic leukemia; Myeloid increases to 71% by age 50 years. malignancies Around 90% of patients with clinical features of SDS have biallellic mutations in the SBDS gene that is Identity mapped to chromosome 7q11.2 region. The incidence of Shwachman-Diamond syndrome Isochromosome 7q consists of two identical copies has been estimated at one case in 77,000 population of the long-arm (q) of chromosome 7 fused at the using comparison cystic fibrosis data. centromere but has lost the short-arm (p) 7p. The subsequent genetic imbalances of the karyotype with Cytogenetics this abnormality results in loss of one copy of 7p and SDS patients often show acquired clonal gain of 7q, thus neoplastic cells apparently suffer chromosomal abnormalities in their bone marrow from an aberrant gene dosage effect (Martens, et al even in the absence of accompanying hematological 1994). disorders. The most frequent is the i(7)(q10), which may Clinics and pathology account up to 44% of the cases with abnormal karyotype followed by monosomy 7 or 7q in 33% Note whereas the del(20)(q11) is found in around 16% of Diseases Hepatosplenic T cell lymphoma (HSTL); patients. Shwachman-Diamond syndrome (SDS); Acute Recent reviews of the literature data have revealed lymphoblastic leukemia (ALL); Myelodysplastic that SDS with the i(7q) do not develop MDS or syndrome (MDS) and Acute myeloid leukemia transform to AML, and rarely accumulate secondary (AML) chromosomal changes during the course of disease. Disease In addition, i(7q) has been rarely seen in SDS Shwachman Diamond syndrome (SDS) patients who developed MDS/AML.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 414 i(7)(q10) Mohamed AN

Figure 1 Hyperdiploid karyotype from a child diagnosed with ALL showing i(7)(q10) i(7q), G-banding - Anwar N Mohamed; Insert: i(7)(q10), R- banding - Jean-Loup Huret (left), Courtesy Christiane Charrin (right).

Genes usually present with isolated hepatosplenomegaly and thrombocytopenia due to malignant T-cell SBDS gene may play an important role in regulating proliferation in the sinusoids of the liver, sinuses and the Fas-mediated apoptosis pathway and may be red pulp of the spleen, and sinuses of the bone responsible for the reduced cellularity in the bone marrow (Belhadj et al 2003) marrow and exocrine pancreas of patients with Shwachman-Diamond syndrome. Mutational Pathology analysis of SBDS gene revealed that SDS is caused Morphology: The cells are monotonous, medium- by two common mutations, (c.183_184TA>CT and sized lymphoid cells with round or slightly irregular c.258+2T>C), in exon 2 of the gene. As the SBDS nuclei, loosely condensed chromatin, and a moderate gene is located on 7q11, bone marrow cells with the amount of pale cytoplasm. Mitotic activity is i(7)(q10) have three copies of this gene. In all eight generally low. Histologic transformation to large cell cases studied the i(7)(q10) carried two copies of the or blastic morphology may occur with disease c.258+2T>c mutation. They suggest that, as the progression. c.258+2T>C mutation still allows the production of Immunophenotype: HSTL is derived from the some amount of normal protein, this may contribute cytotoxic memory T-cells responsible for innate to the low incidence of MDS/AML in SDS patients immunity. Cells express CD2, surface CD3, and with i(7q) ( Minelli et al 2012 ). CD7 but CD56 expression is variable. CD4, CD5 Prognosis and CD8 are not expressed. Most cases of HSTL Studies suggests that SDS with i(7q) represents a express the gamma/delta T cell receptor (TCR), but much less aggressive disease with low risk to rare cases express the alpha/beta TCR. The cytotoxic develop MDS/AML than SDS patients with -7/7q or granule protein TIA-1 is expressed but perforin and complex karyotype. This finding has impacted the granzyme B are absent. management of children with SDS, as hematopoietic Cytogenetics stem cell transplantation is no longer considered in patients with the i(7q) (Cunningham et al 2003). Conventional cytogenetics and fluorescence in situ Disease hybridization (FISH) demonstrate that i(7q) is the primary chromosomal aberration in HSTL detected Hepatosplenic T-cell lymphoma (HSTL) in almost all cases. The most common Note accompanying secondary alterations are trisomy 8, HSTL is a rare and clinically aggressive subtype of loss of sex chromosome, deletion of 11q and gain peripheral T-cell lymphoma, recognized as a distinct extra copies of i(7q). The increase number of i(7q) is clinico-pathological entity in the 2008 WHO associated with cytological features of HSTL classification. Patients are predominantly young men

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progression (.Jonveaux P 1996; Alonsozana EL et al, In a large collaborative study of a newly diagnosed 1997). pediatric ALL, i(7q) was reported in 0.8% of cases. Genes Although i(7q) is found as sole structural abnormality in few cases, usually it accompanies The contribution of i(7q) aberration to the other primary chromosomal changes most frequently pathogenesis of HSTL has been addressed recently. hyperdiploidy followed by t(1;19), t(9;22), and Combined gene expression profiling and array-based t(4;11) (Figure 1). The leukemic cells with i(7q) comparative genomic hybridization (CGH) of have had B-lineage immunophenotype and there several HSTL tumors recently reported by Travert et were no other distinguishing clinical or laboratory al showed downregulation of 7p genes, particularly features in this group (Pui, et al, 1992). The CYCS, IKZF1, HUS1 and CBX3, and upregulation prognostic significance of i(7q) in ALL is still of 7q genes, including the putative oncogene undetermined. PTPN12 (Travert et al 2012). Furthermore, Ferreiro et al studied six HSTL tumors positive for i(7q) Disease including HSTL-derived cell line using high Myeloid malignancies resolution array CGH; all exhibited a constant loss Note of 7p22.1p14.1 and gain of 7q22.11q31.1. On the In MDS and AML, i(7q) is very rare and mostly other hand, the RNA-sequencing did not identify any occurs in the setting of complex chromosomal disease-defining mutation or gene fusion suggesting changes. I(7q) was reported in a child of a transient that chromosome 7 genomic imbalances are the MDS associated with a clonal marrow cytogenetic major events in the pathogenesis of HSTL. Based on abnormality of isochromosome 7q. Without the integrated genomic and transcriptomic data, intervention, the bone marrow cytogenetics reverted Ferreiro et al assumed that loss of 7p sequences is to normal and there was complete hematologic critical for the development of HSTL. This recovery (Leung et al, 2003). Additionally, i(7q) has aberration associates with an enhanced transcription been reported as a sole acquired abnormality in three of CHN2 and overexpression of β2-chimerin, which sporadic cases of Down syndrome with AML (Wong likely affects the NFATC2 related pathway and leads et al 2006). to a proliferative response. Whereas gain of 7q correlates with upregulation of several genes, References including ABCB1, RUNDC3B and PPP1R9A, providing growth advantage to lymphoma cells and Alonsozana EL, Stamberg J, Kumar D, Jaffe ES, Medeiros contributing to their intrinsic chemo-resistance and LJ, Frantz C, Schiffer CA, O'Connell BA, Kerman S, Stass SA, Abruzzo LV. Isochromosome 7q: the primary aggressiveness (Finalet Ferreiro et al 2014). cytogenetic abnormality in hepatosplenic gammadelta T cell Prognosis lymphoma. Leukemia. 1997 Aug;11(8):1367-72 HSTL is a dismal disease. Treatment with various Belhadj K, Reyes F, Farcet JP, Tilly H, Bastard C, Angonin R, Deconinck E, Charlotte F, Leblond V, Labouyrie E, induction regimens has been unsatisfactory, with Lederlin P, Emile JF, Delmas-Marsalet B, Arnulf B, Zafrani variable response rates, high relapse rates, and a ES, Gaulard P. Hepatosplenic gammadelta T-cell short median survival of 8 months. lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood. 2003 Dec Disease 15;102(13):4261-9 Other lymphoproliferaive neoplasms Cunningham J, Sales M, Pearce A, Howard J, Stallings R, Telford N, Wilkie R, Huntly B, Thomas A, O'Marcaigh A, Will Note A, Pratt N. Does isochromosome 7q mandate bone marrow The incidence of isochromosome 7q in other transplant in children with Shwachman-Diamond peripheral T-cell lymphomas has not been well syndrome? Br J Haematol. 2002 Dec;119(4):1062-9 defined. In a single study, using two color FISH Feldman AL, Law M, Grogg KL, Thorland EC, Fink S, Kurtin probes, i(7q) was identified in 4 tumor specimens PJ, Macon WR, Remstein ED, Dogan A. Incidence of TCR from 94 cases; two cases of extranodal NK/T-cell and TCL1 gene translocations and isochromosome 7q in lymphoma, nasal type, and two cases of anaplastic peripheral T-cell lymphomas using fluorescence in situ hybridization. Am J Clin Pathol. 2008 Aug;130(2):178-85 lymphoma kinase-negative anaplastic large cell lymphoma (Feldman et al, 2008). The biologic Finalet Ferreiro J, Rouhigharabaei L, Urbankova H, van der Krogt JA, Michaux L, Shetty S, Krenacs L, Tousseyn T, De significance of i(7q) in ALK- ALCL and NKTL is Paepe P, Uyttebroeck A, Verhoef G, Taghon T, unknown. Vandenberghe P, Cools J, Wlodarska I. Integrative genomic and transcriptomic analysis identified candidate genes Disease implicated in the pathogenesis of hepatosplenic T- Acute Lymphoblastic Leukemia (ALL)

Note cell lymphoma. PLoS One. 2014;9(7):e102977

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Jonveaux P, Daniel MT, Martel V, Maarek O, Berger R. Leukemia. 2009 Apr;23(4):708-11 Isochromosome 7q and trisomy 8 are consistent primary, non-random chromosomal abnormalities associated with Pui CH, Carroll AJ, Raimondi SC, Schell MJ, Head DR, hepatosplenic T gamma/delta lymphoma. Leukemia. 1996 Shuster JJ, Crist WM, Borowitz MJ, Link MP, Behm FG. Sep;10(9):1453-5 Isochromosomes in childhood acute lymphoblastic leukemia: a collaborative study of 83 cases. Blood. 1992 Leung EW, Woodman RC, Roland B, Abdelhaleem M, May 1;79(9):2384-91 Freedman MH, Dror Y. Transient myelodysplastic syndrome associated with isochromosome 7q abnormality. Travert M, Huang Y, de Leval L, Martin-Garcia N, Delfau- Pediatr Hematol Oncol. 2003 Oct-Nov;20(7):539-45 Larue MH, Berger F, Bosq J, Brière J, Soulier J, Macintyre E, Marafioti T, de Reyniès A, Gaulard P. Molecular features Mertens F, Johansson B, Mitelman F. Isochromosomes in of hepatosplenic T-cell lymphoma unravels potential novel neoplasia. Genes Chromosomes Cancer. 1994 therapeutic targets. Blood. 2012 Jun 14;119(24):5795-806 Aug;10(4):221-30 Wong KF, Lam SC, Leung JN. Isochromosome 7q in Down Minelli A, Maserati E, Nicolis E, Zecca M, Sainati L, Longoni syndrome. Cancer Genet Cytogenet. 2006 Jan D, Lo Curto F, Menna G, Poli F, De Paoli E, Cipolli M, 15;164(2):152-4 Locatelli F, Pasquali F, Danesino C. The isochromosome i(7)(q10) carrying c.258+2t>c mutation of the SBDS gene This article should be referenced as such: does not promote development of myeloid malignancies in patients with Shwachman syndrome. Mohamed AN. i(7)(q10). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11):414-417.

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Leukaemia Section Short Communication

Aggressive natural killer leukemia (ANKL) Anwar N Mohamed Cytogenetics laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA; [email protected] Published in Atlas Database: January 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/AggressiveNKcellLeukID1690.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69000/01-2017-AggressiveNKcellLeukID1690.pdf DOI: 10.4267/2042/69000

It is believed that ANKL originates from mature NK Abstract cells. The neoplastic NK cells are typically CD2+, surface CD3-, cytoplasmic CD3ε +, CD56+, and Review of the cytogenetics abnormalities and genes EBV+ with germline configuration of T-cell receptor involved in aggressive natural killer leukemia (TCR) and immunoglobulin (Ig) genes. The (ANKL) which is a rare form of leukemia mostly exclusive expression of CD2 and CD56 and the reported in East Asia. absence of CD3 and TCRs in ANKL reflect its NK- Keywords cell origin. Aggressive natural killer leukemia A high expression rate of CD16 (75%) is also characteristic of ANKL (Li C et al 2014). CD16 is Clinics and pathology usually not expressed in other NK neoplasms, suggesting that CD16 is a specific marker for Disease ANKL. Cases of ANKL are also positive for Aggressive natural killer leukemia (ANKL), cytotoxic molecules and found to have high serum previously known as "large granular lymphocyte levels of CXCR1, CCR5 and soluble Fas ligand, (LGL) leukemia", is a rare neoplastic proliferation of suggesting that the chemokine system plays an mature natural killer (NK) cells described in the important role in the systemic infiltration of NK WHO classification of 2008 as a distinct entity leukemic cells and liver dysfunction (Makishima H separated it from T-cell LGL leukemia . The NK et al, 2007). leukemic infiltration is predominantly systemic, Etiology involving the blood, bone marrow, liver, spleen, and less frequently, lymph nodes. ANKL has a rapidly ANKL is almost always associated with Epstein- fatal clinical course with a median survival of around Barr virus (EBV) infection. EBV plays a role in the 2 months (Suzuki et al, 2004). pathobiology of ANKL and is considered responsible for its aggressive clinical features. Phenotype/cell stem origin Morphologically, the leukemic NK cells are slightly Epidemiology larger than normal LGLs. There is an ample amount This rare leukemia has a distinct geographic of pale or slightly basophilic cytoplasm containing distribution with the most prevalence among East fine or coarse azurophilic granules. Bone marrow Asian populations. A fewer than 200 cases have been shows massive or focal infiltration by NK leukemic described in the literature, as a small series or single cells that can be intermingled reactive histiocytes case report. with hemophagocytosis. In tissue sections, NK cells The disease most commonly affects young to middle show diffuse or patchy destructive infiltrate. aged adults with a median age of 40 years. Both Necrosis, apoptosis, angioinvasion, and sexes are affected with a slight male predominance angiodestruction are common findings. (Lima, M 2013; Zhang et al 2014).

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Clinics investigation by the same group using oligo-array CGH combined with gene-expression profiling of Patients usually present extremely ill with high 32 clinical samples and 7 cell lines were used in an fever, significant weight loss, cytopenia, jaundice effort to delineate the molecular pathogenesis and abnormal liver function. Hepatosplenomegaly is involved NK neoplasms (Karube K et al 2011). The often massive accompanied by lymphadenopathy gains of 1q31.2-44, 7q11.22-36.3, 16p13.3 and but less commonly skin lesions. Involvement of the 11p15.5, and the losses of 6q16.1-27 and 7p15.3- gastrointestinal tract is present in many patients, and 22.2, were found in more than 8 cases (20%). infiltration of leukemic NK cells into the cerebrospinal and peritoneal fluids, with clinical ascites, has been reported. The hemophagocytic Genes involved and syndrome is frequent at diagnosis or during the proteins disease course, resulting from uncontrolled monocyte/macrophage activation in response to Note cytokines produced by the neoplastic NK-cells. Karube at al found that the 6q21 region Despite treatment, ANKL is rapidly progressive encompassing POPDC3, PREP, PRDM1, ATG5, disease and most patients die within few weeks from AIM1, LACE1, and FOXO3 was the most frequently disseminated intravascular coagulation and multi- deleted region of the whole genome. Both FOXO3 organ failure (Liang and Graham 2008; Lima, 2013). and PRDM1expression were down-regulated in most NK-cell neoplasms compared with normal NK Treatment normal cells. The seven candidate genes were ANKL is refractory to the available chemotherapies. transduced into NK cell lines and forced re- L-asparaginase containing chemotherapy regimen expression was induced. Re-expression of FOXO3 followed by allogeneic stem cell transplantation and PRDM1 in NK cell lines suppressed cellular appears to slightly prolong overall survival, but proliferation, but this was not the case after re- relapse is almost inevitable (Ishida F, 2012). expression of the other genes. Therefore, PRDM1 Prognosis and FOXO3 are considered to be tumor suppressor genes play an important role in the pathogenesis of ANKL is a dismal disease with an almost uniform NK-cell neoplasms (Karube K et al 2011). mortality. Survival is measured in days to weeks. Yamanaka, et al study showed that dysregulation of The overall median survival is less than 2 months. microRNAs (miRNAs) has a significant role in the pathogenesis of NK-cell neoplasms. They Cytogenetics demonstrated overexpression of two miRNA " Cytogenetics morphological MIR21and MIR155" in NK-cell lymphoma/leukemia primary specimens and cell Cytogenetic studies on ANKL are limited due to lines. These two miRNAs act through PTEN and rarity of disease, and small samples marked with INPP5D (SHIP1), respectively, to regulate AKT1, a necrosis and mingled with inflammatory cells. serine-threonine kinase involved in cell survival and Despite that, several studies have been reported proliferation. No translocations or genomic some of them using comparative genomic amplifications of the miR-2/17q23 or miR- hybridization (CGH) and loss of heterozygosity 155/12q21 locus have been identified in NK (LOH) techniques (Siu L et al 1999; Ohshima et al neoplasms. Recent reports suggest that EBV 2002). Chromosome abnormalities are found in infection can lead directly to up-regulation of miR- approximately 75% of cases including 21 and miR-155 which might be the first-hit genetic pseudodiploidy (57%), hyperdiploidy (30%), and alterations in NK-cell pathogenesis. Finally, they hypodiploidy (13%). Although no disease-specific proposed targeting miR-21 and/or miR-155 may translocation(s) have not been identified, a complex represent a useful approach to treating NK-cell karyotype with unbalanced rearrangements is found lymphoma/ leukemia (Yamanaka, et al, 2009). in most cases. Deletion of 6q appears to be the most frequent. Other recurrent abnormalities include +X, References i(1q), dup(1q), i(7q), +8, del(13q), del(17p), i(17q), and 11q23 rearrangement (Wong K, 1999; Ishida F, Ko YH, Kim WS, Suzumiya J, Isobe Y, Oshimi K, Nazarullah et al 2015). Deletion of 17p/ TP53 was Nakamura S, Suzuki R. Aggressive natural killer cell leukemia: therapeutic potential of L-asparaginase and confirmed in at least one case with add(17p). allogeneic hematopoietic stem cell transplantation. Cancer Nakashima et al performed BAC-array CGH on 10 Sci. 2012 Jun;103(6):1079-83 cases of ANKL to detect genomic imbalances across Karube K, Nakagawa M, Tsuzuki S, Takeuchi I, Honma K, the whole genome; the recurrent regions Nakashima Y, Shimizu N, Ko YH, Morishima Y, Ohshima K, characteristic of this leukemia, were gain of Nakamura S, Seto M. Identification of FOXO3 and PRDM1 chromosome 1q23-q31 and loss of 7p15.-p22 and as tumor-suppressor gene candidates in NK-cell neoplasms 17p13 (Nakashima et al, 2005). Further

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by genomic and functional analyses. Blood. 2011 Sep Leuk Lymphoma. 2002 Feb;43(2):293-300 22;118(12):3195-204 Siu LL, Wong KF, Chan JK, Kwong YL. Comparative Li C, Tian Y, Wang J, Zhu L, Huang L, Wang N, Xu D, Cao genomic hybridization analysis of natural killer cell Y, Li J, Zhou J. Abnormal immunophenotype provides a key lymphoma/leukemia. Recognition of consistent patterns of diagnostic marker: a report of 29 cases of de novo genetic alterations. Am J Pathol. 1999 Nov;155(5):1419-25 aggressive natural killer cell leukemia. Transl Res. 2014 Jun;163(6):565-77 Suzuki R, Suzumiya J, Nakamura S, Aoki S, Notoya A, Ozaki S, Gondo H, Hino N, Mori H, Sugimori H, Kawa K, Liang X, Graham DK. Natural killer cell neoplasms. Cancer. Oshimi K. Aggressive natural killer-cell leukemia revisited: 2008 Apr 1;112(7):1425-36 large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia. 2004 Apr;18(4):763-70 Lima M. Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis. Orphanet J Rare Dis. 2013 Wong KF, Zhang YM, Chan JK. Cytogenetic abnormalities Jul 1;8:95 in natural killer cell lymphoma/leukaemia--is there a consistent pattern? Leuk Lymphoma. 1999 Jul;34(3-4):241- Makishima H, Ito T, Momose K, Nakazawa H, Shimodaira 50 S, Kamijo Y, Nakazawa Y, Ichikawa N, Ueno M, Kobayashi H, Kitano K, Saito H, Kiyosawa K, Ishida F. Chemokine Yamanaka Y, Tagawa H, Takahashi N, Watanabe A, Guo system and tissue infiltration in aggressive NK-cell YM, Iwamoto K, Yamashita J, Saitoh H, Kameoka Y, leukemia. Leuk Res. 2007 Sep;31(9):1237-45 Shimizu N, Ichinohasama R, Sawada K. Aberrant overexpression of microRNAs activate AKT signaling via Nakashima Y, Tagawa H, Suzuki R, Karnan S, Karube K, down-regulation of tumor suppressors in natural killer-cell Ohshima K, Muta K, Nawata H, Morishima Y, Nakamura S, lymphoma/leukemia. Blood. 2009 Oct 8;114(15):3265-75 Seto M. Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: Zhang Q, Jing W, Ouyang J, Zeng H, George SK, Liu Z. Six different genomic alteration patterns of aggressive NK-cell cases of aggressive natural killer-cell leukemia in a Chinese leukemia and extranodal Nk/T-cell lymphoma, nasal type. population. Int J Clin Exp Pathol. 2014;7(6):3423-31 Genes Chromosomes Cancer. 2005 Nov;44(3):247-55 This article should be referenced as such: Ohshima K, Haraokaa S, Ishihara S, Ohgami A, Yoshioka S, Suzumiya J, Kikuchi M. Analysis of chromosome 6q Mohamed AN. Aggressive natural killer leukemia deletion in EBV-associated NK cell leukaemia/lymphoma. (ANKL). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11):418-420

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Leukaemia Section Review del(6q) Anwar N. Mohamed Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA; [email protected]

Published in Atlas Database: January 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del6qID1248.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69001/01-2017-del6qID1248.pdf DOI: 10.4267/2042/69001 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

leukemia/lymphoma (NK), myelodysplastic Abstract syndrome (MDS), acute myeloid leukemia (AML). Review on deletion of 6q in hematological Epidemiology malignancies, genes involved and clinical significances Deletions affecting chromosome 6q are among the most commonly observed structural aberrations in Keywords lymphoid malignancies (Taborelli et al, 2006). chromosome 6; acute lymphoblastic leukemia; Deletions can include the whole long arm or specific chronic lymphocytic leukemia; Non-Hodgkin regions of 6q. The frequency of 6q deletions varies lymphoma; Hodgkin lymphoma; plasma cell depending on disease histology and methodology myeloma; Waldenström macroglobulinemia; natural used; the deletions have been identified by karyotype killer cell leukemia/lymphoma; myelodysplastic in 4% - 13% of ALL and in 13% - 33% of various syndrome; acute myeloid leukemia. subtypes of lymphoma. However, molecular studies of loss of heterozygosity (LOH) and fluorescence in Identity situ hybridization (FISH) have detected a higher Note frequency of 6q deletions in up to 50% of lymphoma cases and in 30% of ALL cases. Deletions of 6q are characteristic of lymphoid malignancies, but rare in myeloid diseases. In solid Cytogenetics tumor 6q deletions have been reported in melanoma, In the majority of cases, loss of 6q results from an renal cell carcinoma, salivary gland interstitial deletion. Other structural abnormalities adenocarcinoma, ovarian carcinoma and breast leading to 6q deletions such as isochromosome 6p, cancer highlighting the importance of this region in add(6q) or der(6) are less frequent (Figure 1). The 6q cancer development. deletion is usually associated with other karyotypic abnormalities; it is infrequently reported as the sole Clinics and pathology abnormality suggesting that 6q deletion is a secondary change play a relevant role in the Disease progression of the disease. Various hematological malignancies: B- and T- The deletions of 6q are variable in size and have lineages acute lymphoblastic leukemia (ALL), heterogeneous breakpoints. Based on chromosome chronic lymphocytic leukemia (CLL), Non-Hodgkin analysis, Offit et al identified three regions of lymphoma (NHL), Hodgkin lymphoma (HL), minimal cytogenetic deletions in a series of 94 NHL plasma cell myeloma (PCM), Waldenström patients with deleted 6q; these regions were 6q21, macroglobulinemia (WM), natural killer cell 6q23, and 6q25-27 (Offit et al 1993).

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Figure 1. Partial G-banded karyotypes showing various size of 6q deletions in lymphoid malignancies.

Further investigations, Zhang et al attempted to Clinics delineate deletions of 6q in a large series of B- and T-cell NHLs and acute leukemia using a panel of 36 ALL patients with deletions 6q are more likely to YAC FISH probes distributed from 6q12 to 6q27 and have high WBC counts at presentation, mediastinal a centromeric probe of chromosome 6 as internal mass, CNS involvement, T-lineage control. They identified a commonly deleted region immunophenotype, and/or pseudodiploid karyotype. of 3 cM (4-5 Mb) in the 6q21 suggesting that this Prognosis region harbors a putative tumor suppressor gene(s) The clinical data from large studies demonstrated involved in the pathogenesis of both low-grade and that the outcome for patients with or without 6q high-grade NHL as well as ALL (Zhang et al 2000). deletion is similar regardless of NCI risk Disease classification or immunophenotype. Thus, deletion of 6q is not associated with an adverse risk in ALL Acute Lymphoblastic Leukemia (ALL) (Hayashi 1990, Heerema et al 2000). Note Disease Based on banded chromosome, deletions of chromosome 6q occur in 4-13% of B-lineage ALL Chronic Lymphocytic Leukemia (CLL) and in 20-30% of T-lineage ALL. Molecular studies Note of LOH in ALL have shown higher incidences of 6q 6q deletions are found in 3-6% of evaluable CLL deletions in 7-32% of cases with most of the cases by banded chromosomes. However, FISH on deletions are being interstitial. In a large study interphase cells has improved the sensitivity for conducted by Children Cytogenetic Group (CCG), detection of genetic abnormalities in B-CLL. In a Heerema et al reported deletions of 6q in 9% of a large series of 285 CLL patients, two YAC FISH newly diagnosed pediatric ALL; 20% of those probes mapping to 6q21 and 6q27 regions were used. patients had 6q deletion as a sole abnormality and in The deletions of 6q were identified in 7% of patients; other 13% the deletion was seen in a sideline as a the 6q21 region was deleted in all cases whereas the secondary abnormality. Hayashi et al observed a 6q27 region was deleted only in a third of those cases common region of deletion at 6q21 in 45 children (Stilgenbauer S et al, 1999). Furthermore, this study with ALL, and Takeuchi et al described two regions found that patients with 6q deletions had higher of deletion both involving 6q21 among 19 pediatric white blood cell counts and more extensive ALL cases with deleted 6q (Hayashi et al lymphadenopathy but no inferior outcome. In 1990;Takeuchi et al 1998). In contrast the deleted another large study by Cuneo et al, chromosome and region appears to be more proximal in T-ALL at FISH analyses were performed on 217 CLL patients. 6q16. Deletions of 6q occur most often with other The deletion of 6q21 was identified in 20 patients recurring aberrations including 9p, 12p, 13q, 14q or (7.2%) 13 of those (4.7%) had an isolated 6q21 11q23 and/or trisomy of chromosome I6 or 21 but deletion (Cuneo et al 2004). Recent study by Dalsass are less likely to be associated with a hyperdiploid et al using a panel of four probes mapped to 6q16, karyotype (Heerema et al 2000). The use of FISH 6q23, 6q25, 6q27 was performed on 107 CLL cases panel for clinical diagnosis reveals a strong to evaluate the incidence and localization of the association of 6q deletions with 12p ETV6/ RUNX1 deleted region(s) at 6q. positive ALL. They found 6q deletions in 11 cases (10.5%), a higher frequency than the previous reports; in five of

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those cases (4.7%) 6q deletion was a sole during progression of the disease (Taborelli et al abnormality. The additional abnormalities in the 2006). other six cases were trisomy 12, 13q- , 14q-, or In Hodgkin lymphoma, the incidence of 6q deletion complex karyotype. The most frequently deleted is not well determined due to scarcity and low region in their study was in 6q16 (63.6%) followed mitotic index of the Hodgkin and Reed Sternberg (H- by 6q25.2 (36.4%) region (Dalsass et al 2013). RS) cells in culture. Using molecular approach, Re Clinics et al detected allelic losses and imbalances on chromosome 6q in most HL cases (78%). The CLL patients with an isolated 6q21 deletion may detailed mapping using additional microsatellite represent a cytogenetic and clinicobiological entity markers on 6q led to delineation of a 3.3-Mb region characterized by relatively high WBC, high on 6q25. They concluded that allelotyping of single incidence of atypical morphology, classical H-RS cells revealed monoallelic chromosomal immunophenotype with CD38 positivity, deletions and genomic imbalances on 6q that might intermediate incidence of IGVH somatic affect genes critically involved in the pathogenesis hypermutation, and therapy demanding disease. of H-RS cells (Re et al 2003). These features with the clinical outcome place a 6q deletion CLL in an intermediate-risk group (Cuneo Clinics et al 2004). Lately, it was observed that deletion in Cytogenetic analyses indicate that different regions 6q16 appears to be the most frequent region in CLL of loss define distinct clinical-pathological subsets of and could be associated with a more widespread lymphoma. disease when present as the sole abnormality Prognosis (Dalsass et al 2013). Deletion of 6q21 is most frequently associated with Prognosis a high-grade lymphoma and correlates with poor 6q deletion in CLL is suggested to be an intermediate prognosis. risk marker. Disease Disease Waldenström Macroglobulinemia (WM) Lymphoma Note Note Lymphoplasmacytic lymphoma (LPL) is the The frequency of 6q deletions in NHL ranges from pathological designation of WM as proposed by 15-30% of cases by karyotype, mostly accompanied WHO Classification of Tumors. Cytogenetic studies by other chromosomal abnormalities in particular on WM are limited due to rarity of the disease and t(14;18). In a large series of lymphoma cases, Offit low mitotic index of the tumor cells. Deletion of 6q et al found 6q deletions in 20% of cases. They is the most frequent recurrent aberration reported in identified three regions of minimal deletions that 6-16% of WM cases by karyotype. However, FISH may be associated with specific subtypes of using probes targeting different chromosomal lymphomas and different clinical behavior; 6q24- segments on 6q, Schop et al identified deletions of q27 deletion in intermediate-grade NHL; and 6q23 6q in over 50% of WM cases. The minimal deletion deletion noted in low-grade lymphoma lacking region (MDR) was between 6q23 and 6q24.3 and the t(14;18). Taborelli et al characterized 6q deletions in SHPRH gene locus at 6q24, was most frequently 35 malignant HL and NHL lymphomas, using deleted (Schop et al 2006). High resolution array- conventional cytogenetics and FISH probes CGH identified two non-overlapped regions in about targeting 7 molecular regions along 6q. 95% of WM cases covering 1.4 Mb and 3.4 Mb on Conventional cytogenetics revealed a 6q deletion in 6q21-q22.1 (MDR1) and 6q23 (MDR2), 46% of lymphomas while interphase FISH respectively. Potential target genes localized inside demonstrated deletions in 94%; the deletions were those regions are PRDM1 (MDR1) and TNFAIP3 discontinuous, involving nonadjacent molecular (MDR2), two tumor suppressor genes that have been regions. They concluded although 6q deletion is a associated with the pathogenesis of other B-cell common lesion in all types of lymphomas, specific neoplasia (Braggio et al, 2009). deletion patterns seem to characterize different Clinics histological types, suggesting that different tumor suppressor genes play different roles in different WM patients with deletion of 6q are more likely to types of lymphomas. Two specific 6q regions display features of adverse prognosis, such as higher deleted in diffuse large B cell lymphomas but not in levels of beta2-microglobulin and monoclonal follicular lymphomas that may be implicated in the paraprotein and a greater tendency to display anemia disease transformation. On this basis of these and hypoalbuminemia. The incidence of 6q deletions observations, 6q deletion appears to be a dynamic is also higher among WM patients with advanced mutation involving different molecular regions

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disease but not in the premalignant phase of the The variable size and the complexity the deleted disease (Ocio et al, 2006). segments of 6q suggest the presence of multiple and Prognosis potentially cooperating tumor suppressor genes. Thelander et al outlined the deletion patterns of 6q The cohort study from Spain (Ocio et al 2006) using a chromosome 6 specific tile path array in four presented that WM patients with 6q deletions different types of hematological malignances. The required earlier treatment, however, recent study PRDM1, FOXO3A, and HACE1 genes at 6q21 and (Chang etal 2009) found no significant difference in TNFAIP3 gene at 6q23.3 - 24.1 are considered the requirement for treatment between 6q deleted candidate tumor suppressor genes that have been and non-deleted groups, and the time to the treatment reported to be inactivated in B-cell malignancies was also similar between these two groups. (Thelander et al 2006). Other candidate genes However, both studies demonstrated no significant proposed in T- cell neoplasms are EPHA7, difference in overall survival between WM patients CASP8AP2, and GRIK2 at 6q15-q16. with and without 6q deletions. PRDM1 (PR domain containing 1, Disease with ZNF domain) Natural Killer cell Lymphoma/Leukemia (NKLL) Location Note 6q21 NK is a rare group of highly aggressive Note hematolymphoid malignancies characterized by neoplastic proliferation of NK-cells. Deletions of 6q PRDM1 (PR Domain-Containing Protein 1); have been identified in almost 50% of cases with a alternative symbols; BLIMP1 (B Lymphocyte- Induced Maturation Protein 1); PRDIBF1 (Positive common region deletion at 6q21-q25. Molecular Regulatory Domain I-Binding Factor 1) study on 25 NKLL cases identified LOH of 6q in 50% of NK leukemia and in 100% of NK lymphoma Protein with 6q21 region being lost in most cases (Ohshima PRDM1 encodes BLIMP1 which is a zinc finger et al, 2002). PRDM1 and FOXO3 at 6q21 are protein expressed upon plasmacytic differentiation considered to play an important role in the but it is also expressed in T cells, granulocytes, pathogenesis of NK-cell neoplasms. macrophages, epithelial cells, and germ cells. Disease BLIMP1 protein acts as a repressor of beta- interferon (IFNB1) gene expression. One major role Plasma Cell Myeloma (PCM) for BLIMP1 inactivation is to block terminal Note differentiation of B cells by suppressing the Deletions of 6q in PCM have been identified in expression of genes implicated in B cell receptor approximately 1/3 of cases with abnormal signals and cell cycle progression such as BCL6 and karyotype; not seen as a sole abnormality. However; PAX5. This concept is supported by the observation its clinical significance has been addressed yet that introduction of BLIMP1 into a diffuse large B (Mohamed et al 2007). cell lymphoma (DLBCL) cell line leads to G1 cell cycle arrest. Functional studies provided evidences Disease that BLIMP1 is a tumor suppressor gene whose Myeloid Malignancies inactivation may contribute to lymphomagenesis by Note blocking post-GC differentiation of B cells toward Deletion of 6q is an infrequent abnormality seen plasma cells (Kwon et al, 2009; Mandelbaum et al, mostly in conjunction with a complex karyotype. 2010). However, as a sole abnormality it is very rare, Somatic mutations described in isolated cases of MDS and AML (Hirata Somatic mutations that induce inactivation of et al 1992; Gozzetti et al, 2009). The clinical PRDM1 gene occur through a variety of genetic significance of deletion 6q is not clear, due to small means including homozygous deletions, truncating number of patients. The molecular mechanism by or missense mutations, and transcriptional repression which this deletion causing MDS or AML is not by constitutively active BCL6, in ~53% of ABC- addressed, but the most probable mechanism is loss DLBCL. of a tumor suppressor gene located on chromosome arm 6q. Most of these cases with inactive mutations are Genes involved and accompanied by heterogeneous 6q deletions or DNA methylation, indicating that biallelic inactivation proteins occurs frequently. Note

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FOXO3 (forkhead box O3A) function contributes to the constitutive activity of the transcription factor NFKB and the survival and/or Location proliferation of the cells (Schmitz et al 2009). 6q21 Somatic mutations Note TNFAIP3 (A20) is inactivated by somatic mutations FOXO3A (Forkhead Box O3A); alternative symbol; such as base pair deletions, duplication and a single FKHRL1(Forkhead in Rhabdomyosarcoma-Llike base pair insertion all leading to truncated 1); It has at least 3 exons and 2 introns, including an polypeptides lacking the functionally relevant intron located within the coding sequence of the domains. TNFAIP3 somatic mutations were reported forkhead domain that spans at least 90 kb. in 44% of cHL, 36% of primary mediastinal B-cell Protein lymphoma and 25% of marginal zone lymphoma FOXO3A gene belongs to the forkhead family of (Honma et al, 2009). In most mutated cases, both transcription factors which are characterized by a TNFAIP3 alleles were inactivated, including distinct forkhead domain that is highly conserved frequent chromosomal deletions of TNFAIP3/6q23. among various biologic species. A variant of Biallelic deletions of TNFAIP3 have also been FOXO3A gene is associated with longevity in identified in DLBCL and ocular adnexal marginal B- human. FOXO3A functions as a trigger for cell lymphomas. Recently, monoallelic deletions of apoptosis through regulation of a large subset of TNFAIP3 were identified in 38% of WM patients genes involved in DNA repair, cell cycle regulation, and in those cases the TNFAIP3 transcript and apoptosis. Translocation of this gene with the expression levels were significantly lower than in the MLL (KMT2A) was found in a case of secondary group of patients with two copies of the gene. This AML with t(6;11)(q21;q23) . FOXO3 expression suggests that haploinsufficiency of TNFAIP3 can was down-regulated in most NK-cell neoplasms and predispose to the development of WM (Braggio et re-expression of FOXO3 suppressed proliferation of al, 2009). the NK cell line. It was shown that the inhibition of cell growth by FOXO3 is due to the induction of HACE1 (HECT domain and ankyrin apoptosis and cell-cycle arrest. These findings repeat containing E3 ubiquitin indicate that FOXO3 plays a role as a tumor- protein ligase 1) suppressor gene in NK-cell neoplasms (Karube et al Location 2011). 6q16.3 Somatic mutations Note Genomic sequences of protein-coding regions and splice junction were analyzed on 33 clinical samples HECT1 (Domain and Ankyrin Repeat Containing E3 of NK neoplasms (Karube et al, 2011). Somatic Ubiquitin Protein Ligase 1); alternative symbols; missense mutations were found in 3 clinical samples RPD3L1; KIAA1320 but, no mutations were detected in the splice Protein junctions. HACE1 gene encoding a protein belongs to the TNFAIP3 (tumor necrosis factor, HECT family of ubiquitin ligases (HECT E3), which have intrinsic catalytic activity and specificity for alpha-induced protein 3) substrates involved in the regulation of growth and Location apoptosis. HACE1 inhibits the tumor suppressor 6q23.3 gene RARB, ubiquitylates RAC1, which is a rho- Note GTPase involved in cell proliferation and G2/M TNFAIP3 (Tumor Necrosis Factor Alpha Induced cycle progression and degrades cyclin D1 through the control of ROS1. HACE1 is down-regulated in Protein 3); alternative symbol; A20. Wilms tumors and gastrointestinal carcinomas, Protein mediated through hypermethylation of the HACE1 TNFAIP3 encoding A20 is a cytoplasmic zinc finger promoter. In colorectal carcinomas protein that acts as a negative regulator of the nuclear hypermethylation of HACE1 is associated with the factor kappa-B (NFKB) activity and tumor necrosis severity of clinicopathological findings, especially factor (TNF)-mediated programmed cell death. lymph node metastasis. The HACE1 was TNFAIP3 polymorphisms have been associated with demonstrated to be a tumor suppressor gene in NK autoimmune diseases, such as rheumatoid arthritis cell malignancies and to be down-regulated through and systemic lupus erythematosus. Schmitz et al a deletion and DNA hypermethylation, and its demonstrated TNFAIP3 as a novel tumor suppressor alteration may play a crucial role in NK cell gene by showing frequent somatic and clonal lymphomagenesis (Karube et al blood 2011). biallelic inactivation of this gene in HL and B-cell Recently Bouzelfen et al reported HACE1 as a lymphoma. They presented evidence that loss of A20 candidate tumor suppressor gene in B-cells

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lymphomas down-regulated by deletion and CASP8AP2 (caspase 8 associated epigenetic mechanisms; deletions were observed in protein 2) 40% of cases whereas hypermethylation of the HACE1 promoter CpG177 island was found in 60% Location of cases and in all tested B-cell lymphoma lines. 6q15 They concluded that HACE1 can act as a Note haploinsufficient tumor suppressor gene in most B- CASP8AP2 (Caspase 8 Associated Protein 2); cell lymphomas and can be downregulated by alternative symbols FLASH, RIP25. deacetylation of its promoter region chromatin, Protein which makes HACE1 a potential target for HDAC CASP8AP2 gene encodes a protein highly similar to inhibitors (Bouzelfen et al, 2016). the mouse apoptotic protein FLASH. In human Somatic mutations Casp8AP2 associates with CASP8 (caspase 8) to Mutations in HACE1 have not been found in the form the death-inducing signaling complex (DISC) coding or promoter regions of any cancer studied to which regulates the programmed cell death and cell date. cycle survival. EPHA7 (EPH receptor A7) The clinical significance of CASP8AP2 expression was studied in pediatric ALL; patients with low Location CASP8AP2 expression at diagnosis displayed high 6q16.1 minimum residual disease (MRD), high relapse Note rates, lower relapse-free survival and inferior overall EPHA7 (Ephrin type-A receptor 7), alternative survival, in comparison to the higher-expression symbol; HEK11. group (Jiao et al 2012). Protein On the other hand high expression of this gene is EPHA7 gene encoding 998 amino acids protein associated with a greater tendency of leukemic cells belongs to the ephrin receptor subfamily of the to undergo apoptosis. protein-tyrosine kinase family. EPH and EPH- Flotho et al considered the CASP8AP2 expression is related receptors have been implicated in mediating an independent prognostic marker for relapse in developmental events, particularly in the nervous ALL (Flotho C et al., 2006). system. Previous studies showed that the role of this Furthermore, Remke et al identified a deletion of gene in cancer development may be controversial. 6q15-16.1 in 12% of T-ALL patients. Although EPHA7 is upregulated in acute leukemia The deletion included the CASP8AP2 gene whose and in a variety of solid tumors, evidences of Epha7 expression was the single most down-regulated downregulation have been reported in B-cell among other genes in that region. lymphoma, T-cell leukemia, and colon cancer. In The down regulation of CASP8AP2 has been lymphoma, Epha7 downregulation occur by associated with poor early treatment response promoter hypermethylation or loss of heterozygosity (Remke et al 2012). or a combination of both mechanisms. The pattern of The deletion of CASP8AP2 appears to interfere with DNA hypermethylation is similar in various the apoptotic pathways that are targeted by lymphomas as well as in colorectal cancer, chemotherapy used in the induction phase of the suggesting that a common methylation profile is ALL protocol. shared by different type of tumors (Lopez-Nieva et Somatic mutations al 2012). The study by Oricchio et al on follicular While frame shift mutations of this gene have been lymphoma demonstrated that the the expression of describe in solid tumors, no mutations were found in EPHA7 gene is completely lost in over 70% of cases. DLBCL, pointing to a potential haploinsufficiency The loss of expression was affected by differential effect of this gene in lymphoma. promoter methylation caused by extensive CpG island methylation or hemizygous 6q deletions. They GRIK2 (glutamate ionotropic receptor concluded that EPHA7 acts as a tumor suppressor in kainate type subunit 2) follicular lymphoma and is a promising candidate for Location translational development. Specifically, they fused 6q16.3 EPHA7 to the anti-CD20 antibody, to allow Note delivering EPHA7's tumor suppressive activity GRIK2 (Glutamate Ionotropic Receptor Kainate directly to the CD20 expressing lymphoma cells Type Subunit 2); alternative symbols GluK2, MRT6. (Oricchio et al 2010 et al). DNA/RNA Somatic mutations GRIK2 gene comprises 16 exons Oricchio et al study did not detect EPHA7 mutations in the 24 FL cases. Protein

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GRIK2 gene encodes a subunit of a kainate Gozzetti A, Crupi R, Defina M, Bocchia M, Raspadori D, glutamate receptor. Glutamate receptors mediate the Lauria F. Isolated deletion of 6q in a patient with myelodysplastic syndrome. Cancer Genet Cytogenet. 2009 majority of excitatory neurotransmission at many Jul;192(1):51 synapses in the central nervous system. Sinclair et al Hayashi Y, Raimondi SC, Look AT, Behm FG, Kitchingman used FISH to identify a candidate tumor suppressor GR, Pui CH, Rivera GK, Williams DL. Abnormalities of the gene in ALL with 6q deletion. They identified a 4.8- long arm of chromosome 6 in childhood acute lymphoblastic Mb region of minimal deletion and singled out leukemia. Blood. 1990 Oct 15;76(8):1626-30 GRIK2 as the gene most frequently affected by Heerema NA, Sather HN, Sensel MG, Lee MK, Hutchinson deletions of 6q in ALL. This gene was additionally R, Lange BJ, Bostrom BC, Nachman JB, Steinherz PG, analyzed for inactivating mutations in cases of ALL Gaynon PS, Uckun FM. Clinical significance of deletions of carrying heterozygous chromosome 6q deletions and chromosome arm 6q in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group. Leuk for levels of expression in a range of normal and Lymphoma. 2000 Feb;36(5-6):467-78 malignant hematopoietic cells. Expression of GRIK2 was low in normal hematopoietic cells compared Hirata J, Abe Y, Taguchi F, Takatsuki H, Nishimura J, Nawata H. Deletion of chromosome 6q in two cases of acute with levels in brain but was most prominent in those myeloblastic leukemia and a review of the literature. Cancer of T- lineage, and it was consistently detected among Genet Cytogenet. 1992 Feb;58(2):181-5 T-cell leukemias, except in the presence of 6q Honma K, Tsuzuki S, Nakagawa M, Tagawa H, Nakamura deletion. S, Morishima Y, Seto M. TNFAIP3/A20 functions as a novel These observations support the possibility that in at tumor suppressor gene in several subtypes of non-Hodgkin least T-ALL, haploinsufficiency might reduce lymphomas. Blood. 2009 Sep 17;114(12):2467-75 GRIK2 expression below a critical tumor protective Jiao Y, Cui L, Gao C, Li W, Zhao X, Liu S, Wu M, Deng G, threshold level (Sinclair et al, 2004). Li Z. CASP8AP2 is a promising prognostic indicator in pediatric acute lymphoblastic leukemia. Leuk Res. 2012 References Jan;36(1):67-71 Karube K, Nakagawa M, Tsuzuki S, Takeuchi I, Honma K, Bouzelfen A, Alcantara M, Kora H, Picquenot JM, Bertrand Nakashima Y, Shimizu N, Ko YH, Morishima Y, Ohshima K, P, Cornic M, Mareschal S, Bohers E, Maingonnat C, Ruminy Nakamura S, Seto M. Identification of FOXO3 and PRDM1 P, Adriouch S, Boyer O, Dubois S, Bastard C, Tilly H, as tumor-suppressor gene candidates in NK-cell neoplasms Latouche JB, Jardin F. HACE1 is a putative tumor by genomic and functional analyses. 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Identification of copy number abnormalities and inactivating mutations in López-Nieva P, Vaquero C, Fernández-Navarro P, two negative regulators of nuclear factor-kappaB signaling González-Sánchez L, Villa-Morales M, Santos J, Esteller M, pathways in Waldenstrom's macroglobulinemia. Cancer Fernández-Piqueras J. EPHA7, a new target gene for 6q Res. 2009 Apr 15;69(8):3579-88 deletion in T-cell lymphoblastic lymphomas. Carcinogenesis. 2012 Feb;33(2):452-8 Chang H, Qi C, Trieu Y, Jiang A, Young KH, Chesney A, Jani P, Wang C, Reece D, Chen C. Prognostic relevance of Mandelbaum J, Bhagat G, Tang H, Mo T, Brahmachary M, 6q deletion in Waldenström's macroglobulinemia: a Shen Q, Chadburn A, Rajewsky K, Tarakhovsky A, multicenter study. Clin Lymphoma Myeloma. 2009 Pasqualucci L, Dalla-Favera R. BLIMP1 is a tumor Mar;9(1):36-8 suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. 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Ohshima K, Haraokaa S, Ishihara S, Ohgami A, Yoshioka Waldenström macroglobulinemia from IgM monoclonal S, Suzumiya J, Kikuchi M. Analysis of chromosome 6q gammopathy of undetermined significance Cancer Genet deletion in EBV-associated NK cell leukaemia/lymphoma Cytogenet 2006 Sep;169(2):150-3 Leuk Lymphoma 2002 Feb;43(2):293-300 Sinclair PB, Sorour A, Martineau M, Harrison CJ, Mitchell Oricchio E, Nanjangud G, Wolfe AL, Schatz JH, Mavrakis WA, O'Neill E, Foroni L. A fluorescence in situ hybridization KJ, Jiang M, Liu X, Bruno J, Heguy A, Olshen AB, Socci ND, map of 6q deletions in acute lymphocytic leukemia: Teruya-Feldstein J, Weis-Garcia F, Tam W, Shaknovich R, identification and analysis of a candidate tumor suppressor Melnick A, Himanen JP, Chaganti RS, Wendel HG. The gene Cancer Res 2004 Jun 15;64(12):4089-98 Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma Cell 2011 Oct 28;147(3):554-64 Stilgenbauer S, Bullinger L, Benner A, Wildenberger K, Bentz M, Döhner K, Ho AD, Lichter P, Döhner H. Incidence Re D, Starostik P, Massoudi N, Staratschek-Jox A, Dries V, and clinical significance of 6q deletions in B cell chronic Thomas RK, Diehl V, Wolf J. Allelic losses on chromosome lymphocytic leukemia Leukemia 1999 Sep;13(9):1331-4 6q25 in Hodgkin and Reed Sternberg cells Cancer Res 2003 May 15;63(10):2606-9 Taborelli M, Tibiletti MG, Martin V, Pozzi B, Bertoni F, Capella C. Chromosome band 6q deletion pattern in Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A, malignant lymphomas Cancer Genet Cytogenet 2006 Werft W, Breit S, Liu S, Engel F, Wittmann A, Zimmermann Mar;165(2):106-13 M, Stanulla M, Schrappe M, Ludwig WD, Bartram CR, Radlwimmer B, Muckenthaler MU, Lichter P, Kulozik AE. Takeuchi S, Koike M, Seriu T, Bartram CR, Schrappe M, High-resolution genomic profiling of childhood T-ALL Reiter A, Park S, Taub HE, Kubonishi I, Miyoshi I, Koeffler reveals frequent copy-number alterations affecting the TGF- HP. Frequent loss of heterozygosity on the long arm of beta and PI3K-AKT pathways and deletions at 6q15-16 1 as chromosome 6: identification of two distinct regions of a genomic marker for unfavorable early treatment response deletion in childhood acute lymphoblastic leukemia Cancer Blood Res 1998 Jun 15;58(12):2618-23 Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Zhang Y, Matthiesen P, Harder S, Siebert R, Castoldi G, Hartmann S, Mechtersheimer G, Klapper W, Vater I, Calasanz MJ, Wong KF, Rosenwald A, Ott G, Atkin NB, Schlegelberger B. A 3-cM commonly deleted region in 6q21 Giefing M, Gesk S, Stanelle J, Siebert R, Küppers R. in leukemias and lymphomas delineated by fluorescence in TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin situ hybridization Genes Chromosomes Cancer 2000 lymphoma and primary mediastinal B cell lymphoma J Exp Jan;27(1):52-8 Med 2009 May 11;206(5):981-9 Schop RF, Van Wier SA, Xu R, Ghobrial I, Ahmann GJ, Mohamed AN. del(6q). Atlas Genet Cytogenet Oncol Greipp PR, Kyle RA, Dispenzieri A, Lacy MQ, Rajkumar SV, Haematol. 2017; 21(11):421-428. Gertz MA, Fonseca R. 6q deletion discriminates

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Solid Tumour Section Short Communication

Breast: carcinoma with t(1;3)(p36;q13) PRDM16/BBX Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France. [email protected]

Published in Atlas Database: September 2016 Online updated version : http://AtlasGeneticsOncology.org/Tumors/BreastCarct0103PRDM16-BBXID5159.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69002/09-2017-BreastCarct0103PRDM16-BBXID5159.pdf DOI: 10.4267/2042/69002

Abstract DNA / RNA 11 splice variants Review on t(1;3)(p36;q13) PRDM16/BBX in breast Protein cancer, with data on the genes involved. 1276 amino acids and smaller proteins. Contains a Keywords N-term PR domain; 7 Zinc fingers, a proline-rich chromosome 1; chromosome 3; t(1;3)(p36;q13); domain, and 3 Zinc fingers in the C-term. Binds PRDM16; BBX; breast carcinoma DNA. Transcription activator; PRDM16 has an intrinsic histone methyltransferase activity. Clinics and pathology PRDM16 forms a transcriptional complex with Only one case to date, without further data; it is CEBPB. PRDM16 plays a downstream regulatory described as a breast adenocarcinoma, without role in mediating TGFB signaling (Bjork et al., location/morphology details (ductal carcinoma? 2010). PRDM16 induces brown fat determination lobular carcinoma?) (Yoshihara et al 2015). and differentiation. PRDM16 is expressed selectively in the earliest stem and progenitor Epidemiology hematopoietic cells, and is required for the Invasive breast carcinoma is the most common maintenance of the hematopoietic stem cell pool cancer in women, accounting for 22% of all female during development. PRDM16 is also required for cancers. One million women worldwide are survival, cell-cycle regulation and self-renewal in diagnosed with breast cancer every year (Carcangiu neural stem cells (Chuikov et al., 2010; Kajimura et et al. 2005). The most common histologic type of al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016). invasive breast carcinoma is designated as ductal BBX (BBX, HMG-box containing) carcinoma (80% of all cases), with many Location morphologic variants. Invasive lobular carcinoma is 3q13.12 the second major type (5-10%) of breast cancer (Carcangiu et al. 2005). Protein 941 amino acids; high mobility group (HMG)-box Genes involved and protein. These proteins possess a DNA-binding domain. They are involved in transcription, proteins replication and DNA repair. BBX belongs to a novel subfamily of HMG-Box superfamily together with PRDM16 (PR domain containing 16) CIC (Chen et al., 2014). BBX proteins control Location growth and developmental processes of plants, 1p36.32 including seedling photomorphogenesis, and

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 429 Breast: carcinoma with t(1;3)(p36;q13) PRDM16/BBX Huret JL

photoperiodic regulation of flowering (Gangappa Adipose Biology and Beyond. Trends Endocrinol Metab. and Botto, 2014), but their function in animals is 2016 Jan;27(1):11-23. doi: 10.1016/j.tem.2015.11.005. Epub 2015 Dec 11. Review. poorly known. Bbx is highly expressed in the cortex and hippocampus, and may be associated with Chuikov S, Levi BP, Smith ML, Morrison SJ.. Prdm16 promotes stem cell maintenance in multiple tissues, partly central nervous system in zebrafish embryos (Chen by regulating oxidative stress. Nat Cell Biol. 2010 et al., 2014). Homozygous Bbx mutants rats exhibit Oct;12(10):999-1006. doi: 10.1038/ncb2101. Epub 2010 intrauterine growth retardation and male infertility, Sep 12. suggesting that loss of BBX induces apoptosis and Gangappa SN, Botto JF.. The BBX family of plant results in spermiogenesis defects (Wang et al., transcription factors. Trends Plant Sci. 2014 Jul;19(7):460- 2016). 70. doi: 10.1016/j.tplants.2014.01.010. Epub 2014 Feb 24. Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, References Gygi SP, Spiegelman BM.. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, complex. Nature. 2009 Aug 27;460(7259):1154-8. Epub Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a 2009 Jul 29. physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66 Wang CY, Tang MC, Chang WC, Furushima K, Jang CW, Behringer RR, Chen CM.. PiggyBac Transposon-Mediated Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Mutagenesis in Rats Reveals a Crucial Role of Bbx in Prdm16 is required for normal palatogenesis in mice. Hum Growth and Male Fertility. Biol Reprod. 2016 Sep;95(3):51. Mol Genet. 2010 Mar 1;19(5):774-89 doi: 10.1095/biolreprod.116.141739. Epub 2016 Jul 27. Carcangiu, ML ; Casalini, P ; Ménard, S.. Breast tumors: an Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna overview Atlas Genet Cytogenet Oncol Haematol. R, Kim H, Verhaak RG.. The landscape and therapeutic 2005;9(4):331-337. relevance of cancer-associated transcript fusions. Oncogene. 2015 Sep 10;34(37):4845-54. doi: Chen T, Zhou L, Yuan Y, Fang Y, Guo Y, Huang H, Zhou 10.1038/onc.2014.406. Epub 2014 Dec 15. Q, Lv X.. Characterization of Bbx, a member of a novel subfamily of the HMG-box superfamily together with Cic. This article should be referenced as such: Dev Genes Evol. 2014 Dec;224(4-6):261-8. doi: 10.1007/s00427-014-0476-x. Epub 2014 Aug 1. Huret JL. Breast: carcinoma with t(1;3)(p36;q13) PRDM16/BBX. Atlas Genet Cytogenet Oncol Haematol. Chi J, Cohen P. The Multifaceted Roles of PRDM16: 2017; 21(11):429-430.

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Solid Tumour Section Short Communication

Kidney: Renal cell carcinoma with t(X;17)(p11;q25) ASPSCR1/TFE3 Pedram Argani, Marc Ladanyi Department of Pathology, The Johns Hopkins Hospital, Baltimore MD (PA) [email protected]. Published in Atlas Database: August 2016 Online updated version : http://AtlasGeneticsOncology.org/Tumors/RenalCellt0X17ID5035.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69003/08-2016-RenalCellt0X17ID5035.pdf DOI: 10.4267/2042/69003

This article is an update of : Argani P, Ladanyi M. Kidney: t(X;17)(p11.2;q23) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol 2005;9(3)

Abstract Clinics and pathology Review on Renal cell carcinoma with Etiology t(X;17)(p11;q23) CLTC/TFE3, with data on clinics, Unclear. and the genes involved. Keywords Epidemiology Renal cell carcinoma; chromosome X; chromosome Single case report in a 14 year old male. 17; CLTC; TFE3; MiT family Pathology Identity The tumor was bounded by a calcified fibrous pseudocapsule. The tumor had predominantly a Other names solid, compact nested pattern, as islands of tumor Renal cell carcinoma with CLTC-TFE3 gene fusion cells were demarcated by fibrovascular septa. More dyscohesive areas yielded a papillary architecture. Classification Focal calcifications, some in the form of psammoma bodies, were frequent, often associated with hyaline This renal cell carcinoma, of which there is only a nodules. Tumor cells were polygonal with well- single reported case, belongs to the family of Xp11 demarcated, predominantly clear, voluminous translocation renal carcinomas. Xp11 translocation cytoplasm. However, there were scattered areas in renal cell carcinoma (RCCs) harbor gene fusions which the cells were smaller and others where they involving TFE3 transcription factor. demonstrated densely eosinophilic cytoplasm; the The t(6;11) RCCs harbor a specific MALAT1 latter areas had a nested growth pattern and foci of (Alpha) - TFEB gene fusion. central necrosis, somewhat reminiscent of TFEB and TFE3 belong to the same MiT subfamily hepatocellular carcinoma. Mitoses were sparse. of transcription factors. Immunohistochemical (IHC) analysis showed strong Because of similarities at the clinical, morphologic, and diffuse nuclear labeling with a polyclonal immunohistochemical, and genetic levels, the Xp11 antibody to the TFE3 C-terminal portion, as seen in translocation RCCs and t(6;11) RCCs are currently other tumors associated with TFE3 gene fusions. grouped together under the category of MiT family translocation renal cell carcinoma. Since native TFE3 protein is not detectable in non- neoplastic cells by the same assay, this finding is consistent with constitutive expression of a nuclear

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 431 Kidney: Renal cell carcinoma with t(X;17)(p11;q23) Argani P, Ladanyi M CLTC/TFE3

fusion protein containing the TFE3 C-terminal cells did label in one isolated area for Epithelial portion, such as the predicted CLTC-TFE3 protein. Membrane Antigen (EMA). Like most conventional (clear cell) and papillary Underexpression of common epithelial proteins is a RCCs, the tumor contained tumor cells were strongly typical feature of Xp11.2-translocation carcinomas. and diffusely immunoreactive for CD10, showing Surprisingly, the tumor was focally immunoreactive strong cytoplasmic staining with membranous for the melanocytic proteins Melan-A and HMB45 accentuation. However, unlike most typical adult but IHC assays for MiTF and S100 protein were RCCs, IHC with all cytokeratin antibodies (Cam5.2, negative. While unusual, the immunoreactivity for AE1/3, Cytokeratin 7) and the "RCC" monoclonal melanocytic markers can be seen in Xp11 antibody yielded negative reactions, though tumor translocation carcinomas.

Treatment Prognosis Nephrectomy. Unclear.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 432

Kidney: Renal cell carcinoma with t(X;17)(p11;q23) Argani P, Ladanyi M CLTC/TFE3

shaped protein complex that is composed of a trimer Genes involved and of heavy chains (CLTC) each bound to a single light proteins chain. CLTC is a 1675 amino acid residue protein encoded by a gene consisting of 32 exons. Its known Note domains include a N-terminal globular domain The t(X;17)(p11.2;q23) results in a CLTC/TFE3 (residues 1-494) that interacts with adaptor proteins gene fusion. (AP-1, AP-2, b-arrestin), a light chain-binding TFE3 (transcription factor E3) region (residues 1074-1552), and a trimerization domain (residues 1550-1600) near the C-terminus. Location Xp11.23 DNA / RNA Result of the chromosomal The TFE3 gene includes a 5¹ untranslated region, 8 exons, and a 3¹ untranslated region. anomaly Protein Fusion Protein TFE3 is a transcription factor with a basic helix- Description loop-helix DNA binding domain and a leucine In the CLTC-TFE3 fusion, the fusion point on CLTC zipper dimerization domain. TFE3 contains a is at amino acid 932 (corresponding to the end of nuclear localization signal, encoded at the junction of exons 5 and 6, which is retained within all known exon 17), thereby excluding the CLTC trimerization TFE3 fusion proteins. TFE3 protein is 575 amino domain from the predicted fusion protein. As in other TFE3 gene fusions, the nuclear localization acids, and is ubiquitously expressed. and DNA binding domains of TFE3 are retained in TFE3, TFEB, TFEC and Mitf comprise the members CLTC-TFE3. Based on these features and existing of the microphthalmia transcription factor data on other TFE3 fusion proteins, CLTC-TFE3 subfamily, which have homologous DNA binding domains and can bind to a common DNA sequence. may act as an aberrant transcription factor, with the These four transcription factors may homo- or CLTC promoter driving constitutive expression. heterodimerize to bind DNA, and they may have functional overlap. References Argani P, Ladanyi M. Distinctive neoplasms characterised CLTC (clathrin heavy polypeptide) by specific chromosomal translocations comprise a Location 17q23.1 significant proportion of paediatric renal cell carcinomas. Pathology. 2003 Dec;35(6):492-8 Note Clathrin is the major protein constituent of the coat Argani P, Lui MY, Couturier J, Bouvier R, Fournet JC, Ladanyi M. A novel CLTC-TFE3 gene fusion in pediatric that surrounds organelles (cytoplasmic vesicles) to renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene. mediate selective protein transport. Clathrin coats 2003 Aug 14;22(34):5374-8 are involved in receptor-mediated endocytosis and intracellular trafficking and recycling of receptors, This article should be referenced as such: which accounts for its characteristic punctate Argani P, Ladanyi M. Kidney: Renal cell carcinoma with cytoplasmic and perinuclear cellular distribution. t(X;17)(p11;q23) CLTC/TFE3. Atlas Genet Cytogenet Structurally, clathrin is a triskelion (three-legged) Oncol Haematol. 2017; 21(11):431-433.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 433 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Case Report Section

A new case of acute lymphoblastic leukemia with der(X)t(X;8)(q28;q11.2) Tatiana Gindina, Nikolay Mamayev, Vadim Baykov, Olga Slesarchuk, Tatiana Rudakova, Elena Babenko, Boris Afanasyev R.M. Gorbacheva Research Institute of Pediatric Oncology Hematology and Transplantation at First Saint-Petersburg State Medical University named I.P.Pavlov, Saint-Petersburg, Russia; [email protected]

Published in Atlas Database: July 2016 Online updated version : http://AtlasGeneticsOncology.org/Reports/0X08q28q11GindinaID100088.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69004/07-2016-0X08q28q11GindinaID100088.pdf DOI: 10.4267/2042/69004

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Cyto-Pathology Case report on a new case of acute lymphoblastic Classification leukemia with der(X)t(X;8)(q28;q11.2). Phenotype Clinics B-ALL Immunophenotype Age and sex: 19 year(s) old male patient Positive for CD34, CD10, CD19, CD20, CD38. Previous history: no preleukemia , no previous Rearranged Ig Tcr : Not performed. malignancy , no inborn condition of note Pathology : Histopathology of the skin nodules was Organomegaly: hepatomegaly ; splenomegaly ; remarkable for interstitially located groups of small- enlarged lymph nodes (Few reddish skin nodules 5- and middle-sized lymphoid blast-like cells, which 7 mm in diameter); central nervous system were positive for TdT, PAX-5, CD20, CD10, involvement (A tumor-forming mass located in negative for T-cell and myeloid markers and had a temporal lobe of brain at post-transplant relapse.) very high proliferation rate (Ki-67 index above 90 %). Blood C-myc oncogene product was additionally assessed with immunohistochemistry (clone Y69). Over 90% WBC: 1.7X 109/l of blast cells in the skin appeared to be positive for HB: 9.0g/dl ?-myc, although staining pattern was markedly Platelets: 296X 109/l heterogeneous. Bone marrow: Bone marrow smears showed The brain tissue (at post-transplant relapse) hypercellular bone marrow with 54.4% blasts. They contained a dense cellular infiltrate composed of were negative for myeloperoxidase, whereas most of middle-sized PAS-positive blasts with oval or round them positive for PAS stain. The cytoplasm of blasts nuclei, containing 2-3 small nucleoli. Tumor cells was narrow and basophilic. Blasts had rounded were uniformly positive for TdT, CD19, PAX-5, and nucleus and finely dispersed chromatin with well- CD79a and had a very high Ki-67 proliferation contoured nucleoli. Erythropoiesis and myelopoiesis index. C-myc oncogene product was demonstrated were decreased. Erythropoiesis had signs of in over 85% of cells with heterogeneous staining megaloblastosis. Megakaryocytopoiesis: pattern, compatible with indirect c-myc up- hypolobular and polyploid megakaryocytes. regulation.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 434 A new case of acute lymphoblastic leukemia with Gindina T, et al. der(X)t(X;8)(q28;q11.2)

Electron microscopy : Not performed. Other molecular cytogenetics results Diagnosis Common acute lymphoblastic leukemia The unbalanced translocation der(X)t(X;8)(q28;q11.2) was revealed in all Survival metaphases. Other molecular studies Date of diagnosis 09-2012 Technics RT-PCR Treatment: Treatment was started according to Results Leukemic cells were negative for ALL-2009 protocol, containing Daunorubicin, t(1;19)E2A-PBX1, del(1)SIL-TAL1, t(12;21) TEL- VIncristine and L-asparaginase. CNS prophylaxis AML1, and t(9;22) BCR-ABL. therapy consisted intrathecal treatment, whereas cranial irradiation was not used. Comments Complete remission: obtained Here we report a new case of ALL with extremely Treatment related death: no rare abnormality der(X)t(X;8)(q28;q11.2), which Relapse: Yes. Complex medullar and CNS resulted in a partial 8q trisomy. At the first time a extramedullary relapses were diagnosed repeatedly case with der(X)t(X;8)(q28;q11.2) was reported in a on 10 and 13 months after remission. 4-year-old child with Ph-positive ALL who has not The patient received allogeneic HSCT on 04/2014. achieved complete continuous remission [Kaleem et Complete remission was achieved on 06/2014. al, 2000]. Isolated post-transplant CNS relapse was diagnosed This patient had other recurrent chromosomal on 11/2014. abnormalities, such as t(8;14)(q11.2;q32), Phenotype at relapse : Positive for CD34, CD10, t(9;22)(q34;q11) and add(17)(p13). It allows to CD19, CD20, CD38. consider, that the der(X)t(X;8) might be a secondary Status: Dead genetic event. As for our finding is concerned, it Survival: 29 months seems to be primary event, which is responsible for post-transplant isolated CNS relapse. Karyotype Identical chromosome abnormalities in leukemic Sample Bone marrow aspirate, brain tumor mass (by cells at diagnosis and in the cells from brain tumor- stereotactic brain biopsy at post-transplant relapse) forming relapse support the origin of both from common leukemic clone. c-Myc is one of the genes Culture time 24 h, without stimulating agents. located on 8q which may be implicated in disease Banding GTG biology. Immunohistochemical staining for c-myc Results 45,Y,der(X)t(X;8)(q28;q11.2)[20] protein showed positivity of >85% of leukemic cells Karyotype at relapse (at disease onset and at relapse), although with 45,Y,der(X)t(X;8)(q28;q11.2)[20] markedly heterogeneous staining pattern, Other molecular cytogenetics technics compatible with indirect c-myc up-regulation. The Fluorescence in situ hybridisation (FISH) with latter, in turn, could increase proliferative potential whole painting probes for 8 and X chromosomes of leukemic cells as well as their resistance to (Metasystems, Germany). Multicolor banding, using chemotherapy. Finally, trisomy 8 in ALL patients is a multicolor probe for chromosome 8 (Metasystems, considered to be indicative of poor prognosis Germany). [Garipidou et al, 1990].

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 435

A new case of acute lymphoblastic leukemia with Gindina T, et al. der(X)t(X;8)(q28;q11.2)

Figure 1: Histopathological findings in tumor-forming ALL relapse in the brain. Neoplastic cells with lymphoblastic morphology form diffuse dense infiltrate in the brain tissue (A), they are uniformly positive for TdT (B), CD19 (C), and heterogeneously express c-myc (D). Hematoxylin and eosin staining, 400× original magnification (A); IHC for TdT, 400? original magnification (B); IHC for CD19, 200× original magnification (C); IHC for c-myc 400× original magnification (D).

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 436

A new case of acute lymphoblastic leukemia with Gindina T, et al. der(X)t(X;8)(q28;q11.2)

Figure 2: GTG-banded karyotype showing the derivative der(X)t(X;8)(q28;q11.2)

Figure 3: GTG-banding showing the derivative X chromosome; FISH with whole painting probes showing two normal chromosomes 8 (green color) and the derivative der(X)t(X;8) (red and green colors). Multicolor banding of two normal chromosomes 8 and the derivative X chromosome.

References This article should be referenced as such: Gindina T, Mamayev N, Baykov V, Slesarchuk O, Garipidou V, Ysamada T, Grant Prentice HTrisomy 8 in Rudakova T, Babenko E, Afanasyev B. A new case of acute lymphoblastic leukemia (ALL): A case report and acute lymphoblastic leukemia with update of the literature. Leukemia. 1990;4:717-9 der(X)t(X;8)(q28;q11.2). Atlas Genet Cytogenet Oncol Kaleem Z, Shuster JJ, Borowitz MJ. Acute lymphoblastic Haematol. 2017; 21(11):434-437. leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group study. Leukemia. 2000;14:238-240

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(11) 437 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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