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Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3)

Atlas of Genetics and Cytogenetics

in Oncology and Haematology


Editor-in-Chief Jean-Loup Huret (Poitiers, France) Lymphomas Section Editor Antonino Carbone (Aviano, Italy)

Myeloid Malignancies Section Editor Robert S. Ohgami (Stanford, California)

Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands)

Head and Neck Tumors Section Editor Cécile Badoual (Paris, France)

Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts)

Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland)

Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy)

Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil)

DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands)

Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK)

Mitosis Section Editor Patrizia Lavia (Rome, Italy)

WNT pathway Section Editor Alessandro Beghini (Milano, Italy)

B-cell activation Section Editors Anette Gjörloff Wingren and Barnabas Nyesiga (Malmö,

Sweden)

Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France)

Board Members

Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected]

Alessandro

Beghini Department of Health Sciences, University of Milan, Italy; [email protected]

Judith Bovée 2300 RC Leiden, The Netherlands; [email protected]

Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy;

[email protected]

Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected]

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91223 Bretigny-sur-Orge, France; [email protected]

Enric Domingo Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK

[email protected]

Ayse Elif Erson-

Bensan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected]

Ad Geurts van

Kessel

Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB

Nijmegen, The Netherlands; [email protected]

Oskar A. Haas Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer

Research Institute Vienna, Vienna, Austria. [email protected]

Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected]

Nyla Heerema Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA;

[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

Roderick Mc Leod Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig,

Germany; [email protected]

Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected]

Fredrik Mertens Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;

[email protected]

Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected]

Felix Mitelman Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;

[email protected]

Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected]

Stefan Nagel Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig,

Germany; [email protected]

Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected]

Susana Raimondi Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105-

3678, USA; [email protected]

Clelia Tiziana

Storlazzi Department of Biology, University of Bari, Bari, Italy; [email protected]

Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected]

Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected]

Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected]

Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy;

[email protected]

Franck Viguié Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants

Malades, 75015 Paris, France; [email protected]




Volume 23, Number 3, March 2019

Table of contents

Gene Section

POLE (DNA polymerase epsilon, catalytic subunit) 53 Enric Domingo

Leukaemia Section

der(4)t(1;4)(q11-32;q34-35) 56 Adriana Zamecnikova

t(6;17)(p21;p13) 59 Adriana Zamecnikova

62 dic(7;12)(p10-p12;p11-p13) Adriana Zamecnikova

TBL1XR1/MECOM fusion 65 Chrystelle Abdo, Marie Passet, Odile Maarek, Emmanuelle Clappier

t(6;8)(p21;q24) MYC/SUPT3H 68 Muntadhar Al Moosawi, Hélène Bruyère

Chronic Eosinophilic Leukemia-Not Otherwise Specified (CEL-NOS) - Idiopathic Hypereosinophilic Syndrome (IHES) 72 Anwar N. Mohamed

Gene Section Mini Review

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3) 53



POLE (DNA polymerase epsilon, catalytic subunit) Enric Domingo

Department of Oncology, University of Oxford, Oxford, United Kingdom /

[email protected]

Published in Atlas Database: May 2018

Online updated version : http://AtlasGeneticsOncology.org/Genes/POLEID41773ch12q24.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70021/05-2018-POLEID41773ch12q24.pdf DOI: 10.4267/2042/70021

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

Abstract

Review on POLE, with data on DNA, on the protein

encoded, and where the gene is implicated.

Keywords

POLE; DNA repair; DNA replication; DNA

replicase

Identity

Other names: POLE1

HGNC (Hugo): POLE

Location: 12q24.33

Local order: 132,623,762-132,687,359

DNA/RNA

Description

POLE gene is 63.6 kb long and composed of 49

coding exons, where the first and last one also have

a UTR region.

Transcription

The length of the transcript is 7840 bp and results in

a protein of 2286 residues.

Protein

Description

The POLE gene encodes for one of the four subunits

that form Polε (DNA polymerase epsilon) together

with POLE2, POLE3 and POLE4 genes. This

protein is one of the main DNA replicases in

eukaryotes and is responsible of the replication of the

leading strand. POLE contains both the catalytic

active site and the proofreading exonuclease domain

(residues 223-517). Accordingly, the POLE gene

confers to Polε both replicative and 3' to 5' repair

capabilities for the new strand.

Expression

Broadly expressed.

Localisation

Nuclear.

Function

Polε is responsible of the polymerization of the

leading strand during DNA replication in yeast and

humans. It also possesses 3' to 5' exonuclease

capability to repair missincorporated nucleotides

during DNA replication. Polε is also involved in

DNA repair pathways such as mismatch repair

(MMR), base excision repair (BER), nucleotide

excision repair (NER) or double-strand break repair.

Mutations

Germinal

A few missense germline mutations in the

proofreading domain of POLE have been shown to

be pathogenic such as W347C, N363K, D368V,

L424V, P436S or Y458F. These are quite rare in the

population although for unclear reasons they are

more common than similar germline mutations in the

polymerase gene POLD1. These mutations affect the

exonuclease repair of Polε hence resulting in a

mutation rate increase of about 100-fold.

POLE (DNA polymerase epsilon, catalytic subunit) Domingo E


Accordingly, these tumours are usually called

ultramutated.

Somatic

Pathogenic somatic mutations in the proofreading

domain of POLE have been found in some tumour

types at moderate or rare frequencies. Some

mutations in the polymerase domain have been

suggested to be drivers but further research is

required to validate these results.

Implicated in

Different human sporadic cancers

Somatic pathogenic mutations in the proofreading

domain of POLE have been found in 8% of

endometrial tumours and at lower frequencies in

other tumour types such as colorectal, glioblastoma,

ovary, prostate, breast or gastric cancer. These

mutations seem to confer similar phenotypes

regardless of the tumour tissue type. These are

missense, heterozygous mutations where no second

hit by either mutation or LOH seem to be required,

and they are very early events, possibly initiating.

Some mutations are hotspots such as P286R, S297F,

V411L or S459F but other rarer mutations have also

been identified (eg P286H/L, S297Y, F367S,

L424V/I, P436R, M444K, A456P). These mutations

affect the proofreading of the protein resulting in

ultramutation with an overrepresentation of C>A.

More specifically, POLE tumours have mutational

signature 10 as reported by Alexandrov et al, with

extremely prominent TCG>TTG and TCT>TAT

substitutions and transcriptional strand bias. As a

result, there is an overrepresentation of some specific

missense mutations and nonsense mutations. In

addition, it may explain why some cancer driver

genes in POLE tumours tend to show mutations

otherwise relatively uncommon such as R213X in

TP53 or R88Q in PIK3CA. POLE tumours are

hardly ever concomitant with microsatellite

instability, although a few tumours with both

phenotypes have been described, and do not seem to

show chromosomal instability as their karyotype is

nearly diploid.

Disease

Patients with somatic POLE driver mutations are

younger on average, although they have a broad

range of ages. For colorectal cancer, most mutations

are right-sided so they are relatively rare in rectal

cancer.

Prognosis

POLE tumours in endometrial cancer, colorectal

cancer and glioblastoma show excellent prognosis in

early disease. Similar patterns are expected in any

other tumour type although it is not formally proven

due to the low frequency of these mutations. Such

good prognosis is because of very high

immunogenicity with upregulation of immune

checkpoint and other immunosuppressive genes.

Accordingly, POLE proofreading pathogenic

mutation is also a promising candidate biomarker for

checkpoint blockade immunotherapy. They may also

be sensitive to treatment with nucleoside analogs as

they increase the mutation burden to a level where

tumour cells are not viable.

Proofreading-associated polyposis (PPAP)

Disease

Autosomal dominant disease with high risk for

endometrial and/or colorectal adenoma or carcinoma

due to germline mutations in POLE or POLD1

genes.

Prognosis

Probably good prognosis in early disease as found

with POLE somatic mutations, although not

formally proven. Similarly, these patients are likely

to respond to checkpoint blockade immunotherapy.

References Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature 2013 Aug 22;500(7463):415-21

Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, Pons T, González S, Iglesias S, Darder E, Piñol V, Soto JL, Valencia A, Blanco I, Urioste M, Brunet J, Lázaro C, Capellá G, Puente XS, Valle L. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med 2016 Apr;18(4):325-32

Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, Shlien A. Comprehensive Analysis of Hypermutation in Human Cancer. Cell 2017 Nov 16;171(5):1042-1056

POLE (DNA polymerase epsilon, catalytic subunit) Domingo E


Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, Gorman M, Martin L, Howarth KM, Hodgson SV; NSECG Collaborators, Kaur K, Taylor J, Tomlinson IP. DNA polymerase and δ exonuclease domain mutations in endometrial cancer. Hum Mol Genet 2013 Jul 15;22(14):2820-8

Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, Noske A, Amant F, Tomlinson IP, Wild PJ, Lambrechts D, Jürgenliemk-Schulz IM, Jobsen JJ, Smit VT, Creutzberg CL, Bosse T. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst 2014 Dec 12;107(1):402

Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, Fessler E, Medema JP, Boot A, Morreau H, van Wezel T, Liefers GJ, Lothe RA, Danielsen SA, Sveen A, Nesbakken A, Zlobec I, Lugli A, Koelzer VH, Berger MD, Castellví-Bel S, Muñoz J; Epicolon consortium, de Bruyn M, Nijman HW, Novelli M, Lawson K, Oukrif D, Frangou E, Dutton P, Tejpar S, Delorenzi M, Kerr R, Kerr D, Tomlinson I, Church DN. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol 2016 Nov;1(3):207-216

Eggink FA, Van Gool IC, Leary A, Pollock PM, Crosbie EJ, Mileshkin L, Jordanova ES, Adam J, Freeman-Mills L, Church DN, Creutzberg CL, De Bruyn M, Nijman HW, Bosse T. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology 2016 Dec 9;6(2):e1264565

Erson-Omay EZ, alayan AO, Schultz N, Weinhold N, Omay SB, Özduman K, Köksal Y, Li J, Serin Harmanci A, Clark V, Carrión-Grant G, Baranoski J, alar C, Barak T, Coskun S, Baran B, Köse D, Sun J, Bakirciolu M, Moliterno Günel J, Pamir MN, Mishra-Gorur K, Bilguvar K, Yasuno K, Vortmeyer A, Huttner AJ, Sander C, Günel M. Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. Neuro Oncol 2015 Oct;17(10):1356-64

Heitzer E, Tomlinson I. Replicative DNA polymerase mutations in cancer. Curr Opin Genet Dev 2014 Feb;24:107-13

Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E, Perry A, Uppaluri R, Ferguson C, Schmidt RE, Dahiya S, Ansstas G, Mardis ER, Dunn GP. Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy. Cancer Discov 2016 Nov;6(11):1230-1236

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S; CORGI Consortium; WGS500 Consortium, Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Grimes J, Kearsey SE, Thomas HJ, McVean G, Houlston RS, Tomlinson I. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 2013 Feb;45(2):136-44

Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, Church DN. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer 2016 Feb;16(2):71-81

Temko D, Van Gool IC, Rayner E, Glaire M, Makino S, Brown M, Chegwidden L, Palles C, Depreeuw J, Beggs A, Stathopoulou C, Mason J, Baker AM, Williams M, Cerundolo V, Rei M, Taylor JC, Schuh A, Ahmed A, Amant F, Lambrechts D, Smit VT, Bosse T, Graham TA, Church DN, Tomlinson I. Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response. J Pathol 2018 Mar 31

Valle L, Hernández-Illán E, Bellido F, Aiza G, Castillejo A, Castillejo MI, Navarro M, Seguí N, Vargas G, Guarinos C, Juarez M, Sanjuán X, Iglesias S, Alenda C, Egoavil C, Segura , Juan MJ, Rodriguez-Soler M, Brunet J, González S, Jover R, Lázaro C, Capellá G, Pineda M, Soto JL, Blanco I. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet 2014 Jul 1;23(13):3506-12

Van Gool IC, Rayner E, Osse EM, Nout RA, Creutzberg CL, Tomlinson IPM, Church DN, Smit VTHBM, de Wind N, Bosse T, Drost M. Adjuvant Treatment for POLE Proofreading Domain-Mutant Cancers: Sensitivity to Radiotherapy, Chemotherapy, and Nucleoside Analogues. Clin Cancer Res 2018 Mar 20

van Gool IC, Bosse T, Church DN. POLE proofreading mutation, immune response and prognosis in endometrial cancer. Oncoimmunology 2015 Aug 12;5(3):e1072675

This article should be referenced as such:

Domingo E. POLE (DNA polymerase epsilon, catalytic subunit). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3):53-55.

Leukaemia Section Short Communication




der(4)t(1;4)(q11-32;q34-35) Adriana Zamecnikova

Kuwait Cancer Control Center, Kuwait [email protected]

Published in Atlas Database: January 2018

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t01q04q3ID1815.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70022/01-2018-t01q04q3ID1815.pdf DOI: 10.4267/2042/70022


Abstract Unbalanced 1q rearrangements are widely reported

in myeloid and lymphoid malignancies. Among

unbalanced translocations of 1q, der(4)t(1;4)(q11-

32;q34-q35) resulting in complete or partial

trisomies of genes located on 1q is a relatively rare

anomaly.

Keywords

Unbalanced 1q translocations, chromosome gain,

der(4)t(1;4), gene expression.

Figure 1. Partial karyotypes with unbalanced translocation between chromosomes 1 and 4 (A). Fluorescence in situ hybridization with LSI 1p36/1q25 dual color probe (Abott Molecular/Vysis, US) showing the extra copy of 1q (green signal) on

der(4) chromosome (B).

der(4)t(1;4)(q11-32;q34-35) Zamecnikova A


Clinics and pathology

Disease

Myeloid malignancies, multiple myeloma (MM) and

Non-Hodgkin lymphoma.

Myeloid malignancies in 4 (4 males aged 1 to 30

years): 1 refractory anemia with excess blasts-2

(Vundinti et al., 2003), 1 acute myeloblastic

leukemia with minimal differentiation (AML-M0)

(Creutzig et al., 1996), 1 acute erythroleukemia

(AML-M6) (Baumgarten et al., 1993) and 1 acute

megakaryoblastic leukemia (AML-M7) (Martinez-

Climent et al., 1995). 3 of the AML patients were

children with Down syndrome (DS) (aged 1, 2 and 2

years) (Baumgarten et al., 1993; Martinez-Climent et

al., 1995; Creutzig et al., 1996).

Multiple myeloma in 7 (4 males and 3 females;

ages unknown) (Sawyer et al., 1998; Sawyer et al.,

1998; Gutierrez et al., 2000; Lloveras et al.,2004;

Wu et al., 2007; Sawyer et al., 2014; Rack et al.,

2016).

Lymphoid malignancies 1 acute lymphoblastic

leukemia (Lin et al., 1990) (1 female aged 11 years),

1 post-transplant lymphoproliferative disorder (1

male aged 42 years) (Djokic et al., 2006); 10 B-cell

lymphomas (6 males and 4 females aged 39 to 74

years), among them 6 patients with follicular

lymphoma (Nishida et al., 1989; Bastard et al., 1992;

Gray et al., 1997; Itoyama et al., 2002; Aamot et al.,

2007; Narayan et al., 2013), 2 with diffuse large B-

cell lymphoma (DLBCL) (Le Baccon et al., 2001;

Trcic et al., 2010), 2 with mature B-cell neoplasm

(Morgan et al., 1999; Veldman et al., 1997) and there

was an 14 years old female with T-cell anaplastic

large cell lymphoma (Lones et al., 2006).

Epidemiology

15 males and 9 females aged 1 to 74 years (median

42 years).

Prognosis

Reported patients are characterized by complex

karyotypes that likely reflects an inherent

chromosomal instability correlated with a poor

prognosis.

Cytogenetics

Cytogenetics morphological

Various breakpoints on the long arm of chromosome

1; MM and lymphoma patients tend to have more

frequently near-centromeric 1q breakpoints (4 out of

7 MM and 7 out of 10 B-cell lymphoma patients).

Additional anomalies

Sole anomaly in 1 patient with DLBCL (Trcic et al.,

2010), found in association with +8 in 2 AML

patients with Down syndrome (DS) (Baumgarten et

al., 1993; Creutzig et al., 1996) and in 1 with

i(7)(q10) (Martinez-Climent et al., 1995). Found in a

sideline with i(7)(q10) and t(9;22)(q34;q11) in the

ALL patient (Lin et al., 1990), t(14;18)(q32;q21), as

a part of complex karyotypes in 7 out of 10 B-cell

lymphomas (Nishida et al., 1989; Bastard et al.,

1992; Morgan et al., 1999; Le Baccon et al., 2001;

Itoyama et al., 2002; Aamot et al., 2007; Narayan et

al., 2013) and as an additional anomaly to

t(2;5)(p23;q35) in patient with anaplastic large cell

lymphoma (Lones et al., 2006). Found with

del(1)(q21) in 1 (Gutierrez et al., 2000) and as part

of highly complex karyotypes in the remaining

multiple myeloma patients.

Result of the chromosomal anomaly

Fusion protein

Oncogenesis

1q gains represent nonrandom structural aberrations

in hematological malignancies, suggesting the

existence of genes in this chromosomal region that

are important for disease initiation and/or

progression.

Chromosome arm 1q is gene-rich, therefore several

genes on 1q may contribute to disease pathogenesis

that might cooperate in an additive or synergistic

way resulting in their simultaneous downregulation.

der(4)t(1;4)(q11-32;q34-35) has been reported as a

sole karyotype aberration only in one patient, while

it is usually present with additional common

abnormalities or along with complex combinations

of anomalies in most of the reported cases, indicating

that gain of 1q might be relevant for tumor

progression and advanced disease.

References Aamot HV, Torlakovic EE, Eide MB, Holte H, Heim S. Non-Hodgkin lymphoma with t(14;18): clonal evolution patterns and cytogenetic-pathologic-clinical correlations J Cancer Res Clin Oncol 2007 Jul;133(7):455-70

Bastard C, Tilly H, Lenormand B, Bigorgne C, Boulet D, Kunlin A, Monconduit M, Piguet H. Translocations involving band 3q27 and Ig gene regions in non-Hodgkin's lymphoma Blood 1992 May 15;79(10):2527-31

Baumgarten E, Wegner RD, Fengler R, Koch H, Henze G. Partial trisomy 1q, an uncommon chromosomal aberration in erythroleukemia Leuk Lymphoma 1993 Jun;10(3):237-40

Creutzig U, Ritter J, Vormoor J, Ludwig WD, Niemeyer C, Reinisch I, Stollmann-Gibbels B, Zimmermann M, Harbott J. Myelodysplasia and acute myelogenous leukemia in Down's syndrome A report of 40 children of the AML-BFM Study Group Leukemia

Djokic M, Le Beau MM, Swinnen LJ, Smith SM, Rubin CM, Anastasi J, Carlson KM. Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities Genes Chromosomes Cancer

der(4)t(1;4)(q11-32;q34-35) Zamecnikova A


2006 Mar;45(3):313-8

Gray BA, Bent-Williams A, Wadsworth J, Maiese RL, Bhatia A, Zori RT. Fluorescence in situ hybridization assessment of the telomeric regions of jumping translocations in a case of aggressive B-cell non-Hodgkin lymphoma Cancer Genet Cytogenet 1997 Oct 1;98(1):20-7

Gutiérrez NC, Hernández JM, García JL, Almeida J, Mateo G, González MI, Hernández J, Fernández-Calvo J, San Miguel JF. Correlation between cytogenetic abnormalities and disease characteristics in multiple myeloma: monosomy of chromosome 13 and structural abnormalities of 11q are associated with a high percentage of S-phase plasma cells Haematologica 2000 Nov;85(11):1146-52

Itoyama T, Nanjungud G, Chen W, Dyomin VG, Teruya-Feldstein J, Jhanwar SC, Zelenetz AD, Chaganti RS. Molecular cytogenetic analysis of genomic instability at the 1q12-22 chromosomal site in B-cell non-Hodgkin lymphoma Genes Chromosomes Cancer 2002 Dec;35(4):318-28

Le Baccon P, Leroux D, Dascalescu C, Duley S, Marais D, Esmenjaud E, Sotto JJ, Callanan M. Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma Genes Chromosomes Cancer 2001 Nov;32(3):250-64

Lin MT, Tien HF, Wang CH, Chen YC, Lin DT, Lin KH. bcr rearrangements in Philadelphia chromosome-positive acute lymphoblastic leukemia A study of five Chinese patients in Taiwan Cancer Genet Cytogenet

Lloveras E, Granada I, Zamora L, Espinet B, Florensa L, Besses C, Xandri M, Pérez-Vila ME, Millà F, Woessner S, Solé F. Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia Cancer Genet Cytogenet 2004 Jan 1;148(1):71-6

Lones MA, Heerema NA, Le Beau MM, Perkins SL, Kadin ME, Kjeldsberg CR, Sposto R, Meadows A, Siegel S, Buckley J, Finlay J, Abromowitch M, Cairo MS, Sanger WG. Complex secondary chromosome abnormalities in advanced stage anaplastic large cell lymphoma of children and adolescents: a report from CCG-E08 Cancer Genet Cytogenet 2006 Dec;171(2):89-96

Martinez-Climent JA, Lane NJ, Rubin CM, Morgan E, Johnstone HS, Mick R, Murphy SB, Vardiman JW, Larson RA, Le Beau MM, et al. Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia de novo Leukemia 1995 Jan;9(1):95-101

Morgan R, Chen Z, Richkind K, Roherty S, Velasco J, Sandberg AA. PHA/IL2: an efficient mitogen cocktail for cytogenetic studies of non-Hodgkin lymphoma and chronic lymphocytic leukemia Cancer Genet Cytogenet 1999 Mar;109(2):134-7

Narayan G, Xie D, Freddy AJ, Ishdorj G, Do C, Satwani P, Liyanage H, Clark L, Kisselev S, Nandula SV, Scotto L, Alobeid B, Savage D, Tycko B, O'Connor OA, Bhagat G,

Murty VV. PCDH10 promoter hypermethylation is frequent in most histologic subtypes of mature lymphoid malignancies and occurs early in lymphomagenesis Genes Chromosomes Cancer 2013 Nov;52(11):1030-41

Nishida K, Taniwaki M, Misawa S, Abe T. Nonrandom rearrangement of chromosome 14 at band q32 33 in human lymphoid malignancies with mature B-cell phenotype Cancer Res

Rack K, Vidrequin S, Dargent JL. Genomic profiling of myeloma: the best approach, a comparison of cytogenetics, FISH and array-CGH of 112 myeloma cases J Clin Pathol 2016 Jan;69(1):82-6

Sawyer JR, Lukacs JL, Munshi N, Desikan KR, Singhal S, Mehta J, Siegel D, Shaughnessy J, Barlogie B. Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping Blood 1998 Dec 1;92(11):4269-78

Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee F, Barlogie B. Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease Blood 2014 Apr 17;123(16):2504-12

Trci&cacute; RL, Susterci&cacute; D, Kuspili&cacute; M, Jeli&cacute;-Puskari&cacute; B, Fabijani&cacute; I, Kardum-Skelin I. Recurrent chromosomal abnormalities in lymphomas in fine needle aspirates of lymph node Coll Antropol 2010 Jun;34(2):387-93

Veldman T, Vignon C, Schröck E, Rowley JD, Ried T. Hidden chromosome abnormalities in haematological malignancies detected by multicolour spectral karyotyping Nat Genet 1997 Apr;15(4):406-10

Vundinti BR, Madkaikar M, Kerketta L, Jijina F, Ghosh K, Mohanty D, Jijina F. A novel translocation der(4)t(1;4)(q21;q35) and a marker chromosome in a case of myelodysplastic syndrome Cancer Genet Cytogenet 2003 Jul 15;144(2):175-6

Wu KL, Beverloo B, Lokhorst HM, Segeren CM, van der Holt B, Steijaert MM, Westveer PH, Poddighe PJ, Verhoef GE, Sonneveld P; Dutch-Belgian Haemato-Oncology Cooperative Study Group (HOVON); Dutch Working Party on Cancer Genetics and Cytogenetics (NWCGC). Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma Br J Haematol 2007 Feb;136(4):615-23


Zamecnikova A. der(4)t(1;4)(q11-32;q34-35). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3):56-58.





t(6;17)(p21;p13) Adriana Zamecnikova


Published in Atlas Database: January 2018

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0617p21p13ID1814.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70023/01-2018-t0617p21p13ID1814.pdf DOI: 10.4267/2042/70023


Abstract

6p rearrangements in myeloid malignancies are

characterized by heterogeneous breakpoints and

chromosome abnormalities that involve various

partner chromosomes. Balanced chromosome

translocations involving 6p21 are infrequent, among

them the t(6;17)(p21;p13 has been observed only in

sporadic cases.

Keywords

Myeloid malignancies; 6p rearrangements; clonal

evolution; t(6;17)(p21;p13).

Figure 1. Partial karyotypes showing t(6;21)(p21;p13).

t(6;17)(p21;p13) Zamecnikova A


Figure 2. Hybridization with SureFISH PAFAH1B1 probe hybridizing to 17p13.3 showing translocation of 17p sequences to der(6) chromosome (green signal) (A). FISH with SureFISH RUNX2 probe located on 6p21.1 revealed signals on normal and der(6) chromosomes (B). Simultaneous hybridization with SureFISH PAFAH1B1 and RUNX2 probes showed normal signal

pattern on metaphase without t(6;17)(p21;p13) (C) and cohybridization of PAFAH1B1 and RUNX2 probes on der(6) chromosome (red-green signal) (D).

t(6;17)(p21;p13) Zamecnikova A



Disease

Myeloid malignancies

Phenotype/cell stem origin

1 acute myeloblastic leukemia with maturation

(AML-M2) (La Starza et al., 2006), 1

myelodysplastic syndrome (MDS) that terminated in

acute myeloid leukemia without maturation (AML-

M1) and 1 AML with t(3;3)(q21;q26.2) (present

cases, see the Case Reports t(6;17)(p21;p13)

associated with t(3;3)(q21;q26.2) in AML and

t(6;17)(p21;p13) and acquisition of the Philadelphia

chromosome translocation with p190 BCR-ABL1

transcript during the course of myelodysplastic

syndrome).

Note: an identical anomaly was also detected in 2

patients with aneurysmal bone cysts

(Winnepenninckx et al., 2001; Althof et al., 2004).

Epidemiology

Only sporadic cases: 2 males aged 47 and 86 years

and a 25-years old female.

Genetics

Note

Putative candidate genes at 6p21 include CCND3 at

6p21.1 and MHC complex, NOTCH4, BAK1,

FANCE, ETV7, HMGA1, FKBP5 at 6p21.3 (La

Starza et al., 2006).

Cytogenetics


Found in association with +11 in AML-M2 and with

+8 during MDS phase in the present patient in whom

progression from MDS to AML was accompanied

by an appearance of a new clone, t(9;22)(q34;q11)

with the minor p190 BCR/ ABL1 transcript as an

additional anomaly to initial chromosome

abnormalities.

Found in a sideline in AML with t(3;3)(q21;q26.2)

and monosomy 7.


Fusion protein

Oncogenesis

The chromosomal translocation t(6;17)(p21;p13) is

a rare anomaly that has been described in myeloid

malignancies. Found in association with numerical

chromosome anomalies such as +11, +8 and -7,

therefore t(6;17)(p21;p13) is probably a secondary

anomaly arising from a genetically unstable

progenitor cell, acquiring subsequent genetic

events.As these trisomies and monosomy 7 are

known numerical aberrations in MDS and AML, it

is likely that the occurrence of numerical anomalies

may be a major pathogenetic event in these patients.

Alternatively, it is possible that t(6;17)(p21;p13) was

a primary anomaly associated with the early stage of

disease that was replaced by a clone containing

numerical anomalies during the course of a

hematologic malignancy. The acquisition of

t(9;22)(q34;q11) to initial anomalies in 1 patient

indicates, that the Ph is certainly a secondary event

that arose through multiple cytogenetic evolutions,

the final event of which was the development of

t(9;22)(q34;q11).

References Althof PA, Ohmori K, Zhou M, Bailey JM, Bridge RS, Nelson M, Neff JR, Bridge JA. Cytogenetic and molecular cytogenetic findings in 43 aneurysmal bone cysts: aberrations of 17p mapped to 17p13.2 by fluorescence in situ hybridization. Mod Pathol. 2004 May;17(5):518-25

Hillar M, Lott V, Lennox B. Correlation of the effects of citric acid cycle metabolites on succinate oxidation by rat liver mitochondria and submitochondrial particles. J Bioenerg. 1975 Mar;7(1):1-16

La Starza R, Aventin A, Matteucci C, Crescenzi B, Romoli S, Testoni N, Pierini V, Ciolli S, Sambani C, Locasciulli A, Di Bona E, Lafage-Pochitaloff M, Martelli MF, Marynen P, Mecucci C. Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 2006 Jun;20(6):958-64


Zamecnikova A. t(6;17)(p21;p13). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3):59-61.





dic(7;12)(p10-p12;p11-p13) Adriana Zamecnikova


Published in Atlas Database: February 2018

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic07p12pID1816.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70024/02-2018-dic07p12pID1816.pdf DOI: 10.4267/2042/70024


Abstract

Dicentric chromosomes are recurrent finding in

patients with hematological malignancies.

The occurrence of dic(7;12), involving the short

arms of chromosomes 7 and 12 is infrequent and has

been reported mainly in pediatric B-cell acute

lymphoblastic leukemia.

Keywords

Dicentric chromosomes, genomic imbalance, 7p

deletion, tumor suppressor genes.

Clinics and pathology Disease B-cell acute lymphoblastic leukemia (ALL) mainly.

Etiology Myeloid malignancies in 3 (3 males aged 52, 53

and 28 years): 1 refractory anemia with excess of

blasts (RAEB) (Stevens-Kroef et al 2004), 1 acute

myeloblastic leukemia without maturation (AML-

M1) (Tapinassi et al., 2008) and 1 chronic myeloid

leukemia (CML) (de Oliveira et al., 2012) patient.

Figure 1. Partial karyotypes with dic(7;12)(p11.2;p11.2) (A). Fluorescence in situ hybridization (FISH) with LSI ETV6 break apart probe (Abott Molecular/Vysis, US) revealing deletion of ETV6 as a result of dicentric chromosome formation (B). Hybridization

with CEP12 probe (Abott Molecular/Vysis, US) showed the presence of centromeric 12 signals on normal and dic(7;12) chromosomes (C). Simultaneous hybridization with LSI 7q31/CEP7 and CEP12 probes ((Abott Molecular/Vysis, US) confirmed

the presence of chromosome 7 and 12 centromeres on dic(7;12) chromosome on metaphase and interphase cells (DE).

dic(7;12)(p10-p12;p11-p13) Zamecnikova A


Acute lymphoblastic leukemia in 16 (7 males and

9 females aged 1 to 50 years). Of these, 14 had B-

lineage ALL (5 males and 9 females aged 1 to 40

years, median 3 years) (Raimondi et al., 1991;

UKCCG 1992; Pui et al., 1993; Snyder et al., 1999;

Silva et al., 2002; Raimondi et al., 2003; Russell et

al., 2008; Holmfeldt et al., 2013; Olsson et al., 2015;

Marincevic-Zuniga et al., 2016), 1 had T-ALL (an 11

years old male) (Raimondi et al., 1991) and one had

bilineage or biphenotypic leukemia (a 50 years old

male) (Matsumoto et al., 2009).

Epidemiology

19 reported patients (aged 1 to 53 years; median 9

years). Of these, there were 6 adult (aged 28 to 53

years, median 40 years) and 13 pediatric patients

(aged 1 to 16 years, median 3 years).

Prognosis

Simultaneous 7p and 12p deletions, found often

together with complex karyotypes might indicate

genomic instability and an adverse prognostic factor.

Cytogenetics


Unbalanced rearrangement; the formation of a

dicentric chromosome results in partial 7p/12p

monosomies. Most patients had 7p11/12p12 (9

patients) and 7p11/12p11 (8 patients) breakpoints.

Additional anomalies

Sole anomaly in 3 B-ALL patients (Holmfeldt et al.,

2013; Olsson et al., 2015; Marincevic-Zuniga et al.,

2016). Found in a sideline with

del(7)(p11),del(12)(p11) in AML-M1 (Tapinassi et

al., 2008), in association with

(9;22)(q34;q11),i(12)(q10) in CML (de Oliveira et

al., 2012) and complex karyotype in the RAEB

patient (Stevens-Kroef et al., 2004). Found with

del(1q) in 2 (Raimondi et al., 1991; Raimondi et al.,

2003), del(9p) in 1 (Raimondi et al., 1991), del(6q)

in 1 (Raimondi et al., 2003), miscellaneous

anomalies in 3 (Raimondi et al., 1991; Matsumoto et

al., 2009) and with complex karyotypes in 6 ALL

patients (UKCCG 1992; Pui et al., 1993; Snyder et

al., 1999; Silva et al., 2002; Russell et al., 2008;

Olsson et al., 2015).


Fusion protein

Oncogenesis

Structural 12p anomalies are observed in a broad

spectrum of haematological malignancies including

myeloid malignancies and acute lymphoblastic

leukemia. Various aberrations result in an abnormal

12p, including balanced translocations, deletions and

formation of dicentric chromosomes.

Dicentric chromosomes involving 12p are associated

with loss of 12p material that most often include the

ETV6 (TEL) gene localized in 12p13.2.

A lot of partner chromosomes are described; of these

dic(7;12) involving the short arms of chromosomes

7 and 12 is relatively infrequent.

The genetic consequences of this dicentric

chromosome are partial monosomies of 7p and 12p

resulting in concomitant deletions of tumor

suppressor genes from both chromosomes. dic(7;12)

is a rare but recurrent chromosomal abnormality that

has been described mainly in acute lymphoblastic

leukemia of B-lineage and may represent a distinct

cytogenetic subgroup in pediatric ALL.

References Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, Payne-Turner D, Churchman M, Andersson A, Chen SC, McCastlain K, Becksfort J, Ma J, Wu G, Patel SN, Heatley SL, Phillips LA, Song G, Easton J, Parker M, Chen X, Rusch M, Boggs K, Vadodaria B, Hedlund E, Drenberg C, Baker S, Pei D, Cheng C, Huether R, Lu C, Fulton RS, Fulton LL, Tabib Y, Dooling DJ, Ochoa K, Minden M, Lewis ID, To LB, Marlton P, Roberts AW, Raca G, Stock W, Neale G, Drexler HG, Dickins RA, Ellison DW, Shurtleff SA, Pui CH, Ribeiro RC, Devidas M, Carroll AJ, Heerema NA, Wood B, Borowitz MJ, Gastier-Foster JM, Raimondi SC, Mardis ER, Wilson RK, Downing JR, Hunger SP, Loh ML, Mullighan CG. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013 Mar;45(3):242-52

Marincevic-Zuniga Y, Zachariadis V, Cavelier L, Castor A, Barbany G, Forestier E, Fogelstrand L, Heyman M, Abrahamsson J, Lönnerholm G, Nordgren A, Syvänen AC, Nordlund J. PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia. Haematologica. 2016 Jan;101(1):e20-3

Matsumoto Y, Taki T, Fujimoto Y, Taniguchi K, Shimizu D, Shimura K, Uchiyama H, Kuroda J, Nomura K, Inaba T, Shimazaki C, Horiike S, Taniwaki M. Monosomies 7p and 12p and FLT3 internal tandem duplication: possible markers for diagnosis of T/myeloid biphenotypic acute leukemia and its clonal evolution. Int J Hematol. 2009 Apr;89(3):352-358

Olsson L, Albitar F, Castor A, Behrendtz M, Biloglav A, Paulsson K, Johansson B. Cooperative genetic changes in pediatric B-cell precursor acute lymphoblastic leukemia with deletions or mutations of IKZF1 Genes Chromosomes Cancer 2015 May;54(5):315-25

Pui CH, Raimondi SC, Borowitz MJ, Land VJ, Behm FG, Pullen DJ, Hancock ML, Shuster JJ, Steuber CP, Crist WM, et al. Immunophenotypes and karyotypes of leukemic cells in children with Down syndrome and acute lymphoblastic leukemia J Clin Oncol 1993 Jul;11(7):1361-7

Raimondi SC, Privitera E, Williams DL, Look AT, Behm F, Rivera GK, Crist WM, Pui CH. New recurring chromosomal translocations in childhood acute lymphoblastic leukemia Blood 1991 May 1;77(9):2016-22

Russell LJ, Akasaka T, Majid A, Sugimoto KJ, Loraine Karran E, Nagel I, Harder L, Claviez A, Gesk S, Moorman AV, Ross F, Mazzullo H, Strefford JC, Siebert R, Dyer MJ, Harrison CJ. t(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute

dic(7;12)(p10-p12;p11-p13) Zamecnikova A


lymphoblastic leukemia (BCP-ALL) Blood 2008 Jan 1;111(1):387-91

Silva ML, Ornellas de Souza MH, Ribeiro RC, Land MG, Boulhosa de Azevedo AM, Vasconcelos F, Otero L, Vasconcelos Z, Bouzas LF, Abdelhay E. Cytogenetic analysis of 100 consecutive newly diagnosed cases of acute lymphoblastic leukemia in Rio de Janeiro Cancer Genet Cytogenet 2002 Sep;137(2):85-90

Snyder DS, Nademanee AP, O'Donnell MR, Parker PM, Stein AS, Margolin K, Somlo G, Molina A, Spielberger R, Kashyap A, Fung H, Slovak ML, Dagis A, Negrin RS, Amylon MD, Blume KG, Forman SJ. Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission Leukemia 1999 Dec;13(12):2053-8

Stevens-Kroef M, Poppe B, van Zelderen-Bhola S, van den Berg E, van der Blij-Philipsen M, Geurts van Kessel A, Slater R, Hamers G, Michaux L, Speleman F, Hagemeijer A. Translocation t(2;3)(p15-23;q26-27) in myeloid

malignancies: report of 21 new cases, clinical, cytogenetic and molecular genetic features Leukemia 2004 Jun;18(6):1108-14

Tapinassi C, Gerbino E, Malazzi O, Micucci C, Gasparini P, Najera MJ, Calasanz MJ, Odero MD, Pelicci PG, Belloni E. A new dic(7;12)(p12 21;p12 2) chromosome aberration in a case of acute myeloid leukemia

Translocations involving 9p and/or 12p in acute lymphoblastic leukemia. United Kingdom Cancer Cytogenetics Group (UKCCG) Genes Chromosomes Cancer 1992 Oct;5(3):255-9

de Oliveira FM, de Carvalho Palma L, Falcão RP, Simões BP. A new dic(7;12)(p12 21;p12 2) and i(12)(q10) during the lymphoid blast crisis of patient with Ph+ chronic myeloid leukemia


Zamecnikova A. dic(7;12)(p10-p12;p11-p13). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3):62-64.





TBL1XR1/MECOM fusion Chrystelle Abdo, Marie Passet, Odile Maarek, Emmanuelle Clappier

Service d'Hématologie biologique, hôpital Saint-Louis, AP-HP; [email protected];

[email protected]; [email protected]

Published in Atlas Database: April 2018

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del3q26TBL1XR1-MECOMID1823.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70025/04-2018-del3q26TBL1XR1-MECOMID1823.pdf DOI: 10.4267/2042/70025


Abstract A novel TBL1XR1/MECOM fusion was identified

in a patient with acute undifferentiated leukemia.

Keywords

chromosome 3 ; MECOM; TBL1XR1; acute

undifferentiated leukemia; deletion 3q26.2q26.32 ;

fusion gene

Identity

del(3)(q26.2q26.3) TBL1XR1/MECOM


Disease

Acute undifferentiated leukaemia (classified in acute

leukaemias of ambiguous lineage)


This leukemia was CD34+high, CD38+ and

CD117+/- but negative for all lineage specific

markers (cMPO-, CD13-, CD33-, CD7-, cCD3-,

cCD79a-, CD19-, cCD22- cCD79a-).

Epidemiology

Only one case described, a 44-year-old-man (present

report)

Cytology

Undifferentiated blasts, without criteria specific for

either lineage (myeloid or lymphoid)

Treatment

The patient was treated according to the GRAALL-

2014 protocol for adult acute lymphoblastic

leukemia including induction, salvage course, then

consolidation blocks and allo-HSCT transplantation.

Cytogenetics

Note

No abnormality detected on conventional karyotype:

46,XY[20]

Probes

XL MECOM D-5059-100-OG

Genes involved and proteins

MECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplasic Syndrome 1 (MDS1/EVI1))

Location

3q26.2

Note

MECOM is also known as EV1 or PRDM3.

MECOM means MDS and EVI1 complex locus.

DNA/RNA

EVI1 locus spans approximately 65 kb and contains

16 exons.

MDS1 locus spans approximately 500 kb and

contains 4 exons.

The MDS1/EV1 transcript results from intergenic

splicing of the second exon of MDS1 (telomere) to

the second exon of EVI1 (centromere)

TBL1XR1/MECOM fusion Abdo C, et al.


FISH using a locus specific break-apart MECOM 3q26 probe (Metasystem XL D-5059-100-OG) confirmed the deletion at 3q26.2

locus telomeric to MECOM (loss of green signal).

Protein

MDS1/EVI1 protein contains a positive regulator

domain (PR-domain) acting as a tumor-suppressor,

a repression domain between two sets of several zinc

finger motifs, and an acidic domain at its C-terminus.

It is a nuclear transcriptional regulator involved in

differentiation, proliferation and maintenance of

hematopoietic stem cells. Deregulation of the proto-

oncogene MECOM by the 3q rearrangements (inv3

or t(3;3)) reposition a distal GATA2 enhancer,

inducing an aberrant expression of EVI1 and

conferring GATA2 fonctional haploinsufficiency

(Gröschel et al, 2014). This mechanism is implicated

in leukemogenesis of MDS/ AML with an extremely

poor treatment outcome.

TBL1XR1 (Transducin beta like 1 X-linked receptor 1)

Location

3q26.32

Note

TBL1XR1 is also known as MRD41

DNA/RNA

TBL1XR1 locus contains 18 exons.

It is a member of the WD40 repeat-containing gene

family

Protein

The TBL1XR1 gene encodes a protein of 514 amino

acids, which is a component of both N-CoR (nuclear

receptor corepressor) and SMRT (silencing mediator

of retinoid acid and thyroid hormone receptor)

repressor complexes, which targeting nuclear

receptor to repress transcription. TBL1XR1 is also

required for transcriptional activation by many

transcription factors (Li et al, 2015). The protein

contains a LisH domain (Lis1 homology domain)

and a F-box like domain in its N-terminal region, and

8 WD40 repeats at the carboxy-terminus. It seems to

play a role in the maintenance of hematopoietic stem

cells (Li et al, 2015). TBL1XR1 mutations and

rearrangements have been described in several

lymphoid malignancies including diffuse large B cell

lymphoma, acute lymphoblastic leukemia and acute

promyelocytic leukemia (Heinen et al, 2016).

TBL1XR1/MECOM fusion Abdo C, et al.



Hybrid gene

Description

5'TBL1XR1-3'MECOM. TBL1XR1 exon 7 fused

in-frame with MECOM exon 9 or 10.

Detection

RT-PCR using MECOM and TBL1XR1 primers.

Fusion protein

Schematic representations of TBL1XR1 and MECOM proteins and TBL1XR1/MECOM putative fusion proteins.

Description

The TBL1XR1/MECOM rearrangement may result

in a putative hybrid protein containing the N-

terminal portion (234 first aminoacids) of TBL1XR1

with its LisH, F-box and part of WD repeat domains

and the C-terminal portion (381 last aminoacids) of

MECOM retaining one set of zinc finger motif and

the acidic domain.

References Delwel R, Funabiki T, Kreider BL, Morishita K, Ihle JN. Four of the seven zinc fingers of the Evi-1 myeloid-transforming gene are required for sequence-specific binding to GA(C/T)AAGA(T/C)AAGATAA. Mol Cell Biol. 1993 Jul;13(7):4291-300

Goyama S, Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, Chiba S, Kurokawa M. Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. Cell Stem Cell. 2008 Aug 7;3(2):207-20

Gröschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BAM, Erpelinck C, van der Velden VHJ, Havermans M, Avellino R, van Lom K, Rombouts EJ, van Duin M, Döhner K, Beverloo HB, Bradner JE, Döhner H, Löwenberg B, Valk PJM, Bindels EMJ, de Laat W, Delwel R. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell. 2014 Apr 10;157(2):369-381

Heinen CA, Jongejan A, Watson PJ, Redeker B, Boelen A, Boudzovitch-Surovtseva O, Forzano F, Hordijk R, Kelley R, Olney AH, Pierpont ME, Schaefer GB, Stewart F, van Trotsenburg AS, Fliers E, Schwabe JW, Hennekam RC. A specific mutation in TBL1XR1 causes Pierpont syndrome. J Med Genet. 2016 May;53(5):330-7

Li JY, Daniels G, Wang J, Zhang X. TBL1XR1 in physiological and pathological states. Am J Clin Exp Urol. 2015;3(1):13-23

Maicas M, Vázquez I, Alis R, Marcotegui N, Urquiza L , Cortés-Lavaud X , Cristóbal I ,Garcèa-Sánchez MA, D. Odero MD. The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells. Biochim Biophys Acta. 2017 Jun;1860(6):721-729

Wieser R.. The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene 2007 Jul 15;396(2):346-57. Epub 2007 Apr 20.


Abdo C, Passet M, Maarek O, Clappier E. TBL1XR1/MECOM fusion. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3):65-67.





t(6;8)(p21;q24) MYC/SUPT3H Muntadhar Al Moosawi, Hélène Bruyère

Hematopathology, Department of Pathology and Laboratory Medicine, [email protected]

(MAM); Vancouver General Hospital Cytogenetics Laboratory, Department of Pathology and

Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada,

[email protected] (HB)

Published in Atlas Database: May 2018

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0608p21q24SUPT3H-MYCID2987.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70026/05-2018-t0608p21q24SUPT3H-MYCID2987.pdf DOI: 10.4267/2042/70026


Abstract Review on t(6;8)(p21;q24), with data on clinics, and

the genes involved.

Keywords

Blastic, plasmacytoid, dendritic, cell, neoplasm,

t(6;8), chromosome 6, chromosome 8

Identity

Figure 1: t(6;8)(p21.1;q24.2), G-banding. Courtesy Hélène Bruyère.


Disease

Blastic plasmacytoid dendritic cell neoplasm

(BPDCN)


Disease derives from precursors of plasmacytoid

dendritic cells.

Epidemiology

The t(6;8) has been found in a limited subset of

BPDCN: Less than 10 cases reported to date.

Preponderance of male cases (7/8 to date).

Average age 65 years, in keeping with BPDCN's

mean/median age of 61-67 (WHO Classification of

Tumours of Hematopoietic and Lymphoid Tissues,

2017).

Clinics

In general, BPDCN is an aggressive disease that

most commonly involves the skin but can also

infiltrate the bone marrow and peripheral blood as

well as the lymph nodes.

Seven out of eight cases of t(6;8) reported so far had

bone marrow involvement based on bone marrow

biopsy (Boddu et al., 2018; Momoi et al., 2002;

Takiuchi et al., 2012; Nakamura et al., 2015; Fu et

al., 2013; personal communication).

One case reported by Leroux et al. in 2002 showed

an extensive peripheral blood involvement with 95%

circulating blasts.

Although a bone marrow biopsy was not performed,

the heavy involvement of peripheral blood,

indicating bone marrow involvement, was sufficient

to make the diagnosis.

Cytogenetics

Found with additional abnormalities in all cases, as

the sole abnormality in the stemline in one case

(Boddu et al., 2018), as a secondary abnormality in

one case (Boddu et al., 2018), as part of a complex

karyotype in 5/8 cases.

t(6;8)(p21;q24) MYC/SUPT3H Al Moosawi M and Bruyère H


Table 1: Cases of BPDCN with t(6;8)(q21;q24). BM: bone marrow, LN: lymph node, PB: peripheral blood.

Figure 2: FISH image showing the presence of a normal (fused) MYC signal and separated 5'MYC signal from 3'MYC signal.

Figure 3: Image from immunohistochemistry with MYC antibody on bone marrow cells.



Of note, cytogenetic abnormalities are present in

about two-thirds of BPDCN cases, involving

chromosomes 5q34, 12p13, 13q13-21, 15q, and loss

of chromosome 9 (WHO Classification of Tumours

of hematopoietic and lymphoid tissues, 2017).

Prognosis

The prognosis of BPDCN is usually poor in adults

(Bekkenk et al., 2004, Suzuki et al., 2005) and this

appears to be true for cases with t(6;8). Two cases

with this translocation failed to respond to treatment,

the overall survival being 3 and 12 months

respectively (Boddu et al., 2018). One patient

relapsed three months after the initial diagnosis and

treatment and received multiple lines of

chemotherapy but eventually died because of septic

shock nine months after the initial diagnosis (Momoi

et al., 2002). The only female reported so far with

t(6;8) received palliative chemotherapy and died two

months after the initial diagnosis. Another patient

responded to treatment and tumor cells in the

peripheral blood disappeared in day 8; however, the

patient died of septic shock on day 16 (Takiuchi et

al., 2012). A 29-year-old male patient who was

diagnosed with BPDCN with complex karyotype

including t(6;8) received ALL-based chemotherapy

achieved complete morphological remission by day

24 of treatment and has been on sustained remission

at least until this paper was written (personal

communication).

Cytogenetics The t(6;8)(p21.1;q24.2) is identified by conventional

karyotyping.

Note: Other translocations involving 8q24 have been

reported in BPDCN: t(8;14)(q24;q32),

t(X;8)(q24;q24), t(3;8)(p25;q24) (Boddu et al.,

2018; Nakamura et al., 2015)

Genes involved and proteins

MYC

Location

14q23.3

DNA/RNA

DNA/RNA: CMYC is composed of three exons

spanning over 4 kb with the second and third exons

encoding most MYC protein.

SUPT3H

Location

6p21.1

DNA/RNA

DNA/RNA: SUPT3H is composed of 22 exons with

a size of 570 kb.

Protein

399 amino acids and 44 kDa.


Hybrid gene

Description

The translocation has been shown to result in a split

MYC signal when using a commercial MYC break-

apart FISH probe (Nakamura et al., 2015, Boddu et

al., 2018, Fu et al., 2013). Involvement of the MYC

gene has also be inferred from the positive MYC

immunochemistry observed on bone marrow slides

(Nakamura et al., 2015, Boddu et al., 2018).

Molecular analysis of the 8q24 breakpoint showed

that it occurred in the PVT1 gene on chromosome 8

(Nakamura et al., 2015; Fu et al., 2013; Jardin et al.,

2009). PVT1 is located 149 kb telomeric to MYC. It

is a long non-coding RNA located within the interval

between the 5' MYC probe and 3'MYC commercial

probes used to identify MYC rearrangements. Jardin

et al. in 2009 found, in BPDCN, a 5.6-Mb interstitial

deletion on 8q24 involving PVT1 bringing MYC

oncogene adjacent to miR-30b/30c leading to

possible up-regulation of these genes.

References Martín-Martín L, López A, Vidriales B, Caballero MD, Rodrigues AS, Ferreira SI, Lima M, Almeida S, Valverde B, Martínez P, Ferrer A, Candeias J, Ruíz-Cabello F, Buadesa JM, Sempere A, Villamor N, Orfao A, Almeida J. Classification and clinical behavior of blastic plasmacytoid dendritic cell neoplasms according to their maturation-associated immunophenotypic profile. Oncotarget. 2015 Aug 7;6(22):19204-16

Momoi A, Toba K, Kawai K, Tsuchiyama J, Suzuki N, Yano T, Uesugi Y, Takahashi M, Aizawa Y. Cutaneous lymphoblastic lymphoma of putative plasmacytoid dendritic cell-precursor origin: two cases. Leuk Res. 2002 Jul;26(7):693-8

Nakamura Y, Kayano H, Kakegawa E, Miyazaki H, Nagai T, Uchida Y, Ito Y, Wakimoto N, Mori S, Bessho M. Identification of SUPT3H as a novel 8q24/MYC partner in blastic plasmacytoid dendritic cell neoplasm with t(6;8)(p21;q24) translocation. Blood Cancer J. 2015 Apr 10;5:e301

Pagano L, Valentini CG, Pulsoni A, Fisogni S, Carluccio P, Mannelli F, Lunghi M, Pica G, Onida F, Cattaneo C, Piccaluga PP, Di Bona E, Todisco E, Musto P, Spadea A, D'Arco A, Pileri S, Leone G, Amadori S, Facchetti F; GIMEMA-ALWP (Gruppo Italiano Malattie EMatologiche dell'Adulto, Acute Leukemia Working Party).. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study. Haematologica. 2013 Feb;98(2):239-46

Suzuki R, Nakamura S, Suzumiya J, Ichimura K, Ichikawa M, Ogata K, Kura Y, Aikawa K, Teshima H, Sako M, Kojima H, Nishio M, Yoshino T, Sugimori H, Kawa K, Oshimi K; NK-cell Tumor Study Group.. Blastic natural killer cell lymphoma/leukemia (CD56-positive blastic tumor):



prognostication and categorization according to anatomic sites of involvement. Cancer. 2005 Sep 1;104(5):1022-31.

Takiuchi Y, Maruoka H, Aoki K, et al.,. Leukemic manifestation of blastic plasmacytoid dendritic cell neoplasm lacking skin lesion: a borderline case between acute monocytic leukemia J. Clin. Exp. Hematopathol. 2012 52(2):107-111.

Wiesner T, Obenauf AC, Cota C, Fried I, Speicher MR, Cerroni L.. Alterations of the cell-cycle inhibitors p27(KIP1)

and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms. J Invest Dermatol. 2010 Apr;130(4):1152-7


Al Moosawi M, Bruyère H. t(6;8)(p21;q24) MYC/SUPT3H. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3):68-71.

Leukemia Section Review




Chronic Eosinophilic Leukemia-Not Otherwise Specified (CEL-NOS)

Idiopathic Hypereosinophilic Syndrome (IHES) 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: June 2018

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ChrEosinoLeukID1340.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70027/06-2018-ChrEosinoLeukID1340.pdf DOI: 10.4267/2042/70027


Abstract Chronic eosinophilic leukemia (CEL) not otherwise

specified (NOS) and idiopathic hypereosinophilic

syndrome (HES) are rare hematologic disorders

characterized by chronic, unexplained eosinophilia

with manifestation of organ involvement related to

eosinophil infiltration, in the absence of evidence of

secondary causes such as parasitic infestation,

allergy, or neoplasm. Neither CEL-NOS nor

idiopathic HES show Ph chromosome/ BCR-ABL

fusion gene or other genetically defined entities such

as PDGFRA, PDGFRB, or FGFR1 abnormalities.

Keywords

Chronic eosinophilic syndrome, hypereosinophilia,

CEL-NOS, idiopathic HES


Disease

Chronic Eosinophilic Leukemia not otherwise

specified (CEL-NOS) CEL-NOS is a myeloproliferative neoplasm caused

by autonomous clonal proliferation of eosinophilic

precursors that result to increased number of

eosinophils in peripheral blood, bone marrow and

peripheral tissues with eosinophilia being the most

striking feature. The key criteria for diagnosis of

CEL-NOS are peripheral blood hypereosinophilia

(>1.5 -10 9/L), an increased number of myeloblasts

in blood and bone marrow (

The diagnostic criteria of CEL-NOS based on the

revised WHO 2016 include: 1 Marked eosinophilia, count of ≥ 1.5x109/L in

peripheral blood persisting for more than 6 months

2 An increase of myeloblasts in peripheral blood

>2% or bone marrow myeloblasts < 20% of all

nucleated cells

3 There is an evidence of clonality of eosinophils

verified by detection of clonal cytogenetic or

molecular genetic abnormality, or by demonstration

of skewed expression of X chromosome genes

4 Does not meet the WHO diagnostic criteria for

chronic myeloid leukemia (CML), or other

myeloproliferative neoplasms ( PV, ET, PMF,

systemic mastocytosis) or MDS/MPN ( CMML or

atypical CML)

5 No t(9;22) BCR / ABL1 fusion; No rearrangement

of PDGFRA, PDGFRB, or FGFR1; no PCM1 /

JAK2, ETV6 /JAK2, or BCR/JAK2 fusion gene

6 No inv(16) / CBFB rearrangement and other

diagnostic features of acute myeloid leukemia

(AML).

Chronic Eosinophilic Leukemia-Not Otherwise Specified (CEL-NOS) - Idiopathic Hypereosinophilic Syndrome (IHES)

Mohamed AN


Idiopathic hypereosinophilic syndrome (IHES) If clonality of eosinophils cannot be proven and there

is no increase in myleoblasts, then the diagnosis is

idiopathic HES (Bain et al, 2016). Idiopathic HES is

a diagnosis of exclusion when secondary and clonal

causes of eosinophilia are ruled out (Bain, 2004 A;

Bain, 2004B). It is defined as sustained eosinophilia

≥ 1.5X10 9 in peripheral blood for at least 6 months

with signs of organ involvement and dysfunction in

which the underlying cause remains unknown

(Figure 1). There is no increase in blasts and no

evidence of eosinophil clonalilty. Yet, the advances

in molecular diagnostic technologies have

demonstrated that many patients who had previously

been considered as having idiopathic HES can now

be found to have an eosinophilic leukemia since

clonal molecular genetic abnormality can be

demonstrated (Gotlib and Cools 2008). Moreover,

transformation to acute myeloid leukemia in some

patients with idiopathic HES also provides evidence

that the disorder was likely from the start to be a

clonal CEL (Wang et al, 2016).

Epidemiology

The incidence of CEL-NOS is not well-defined due

to rarity of the disorders and difficulty to distinguish

CEL-NOS from idiopathic HES. Recently reported

study using the Surveillance, Epidemiology, and End

Results shows an incidence of 0.036 per 100,000

person-years, but this calculation included patients

with HES and other clonal CEL (Crane et al, 2010).

CEL-NOS affect more males than females with a

reported median age of diagnosis in the sixty (Bain

et al, 2016; Wang et al 2016). The epidemiology

features of idiopathic HES remain undefined.

Clinics

Patients may present with various combinations of

symptoms and signs of end-organ damage mediated

by eosinophils. In many patients, the onset of

symptoms is insidious, and eosinophilia is detected

incidentally. However in others, the initial

manifestations are severe and life-threatening due to

the rapid progression of cardiovascular or neurologic

complications. The common constitutional

symptoms that patients experience are fatigue,

cough, dyspnea, myalgia, fever, diarrhea, rash and/or

rhinitis. Progressive heart failure is an example of

eosinophil-mediated organ injury which is the major

cause of morbidity and mortality in these patients.

Endocardial damage with resulting platelet thrombus

can lead to mural thrombi and increased embolic

risk. In the later fibrotic stage, endomyocardial

fibrosis can evolve to a restrictive cardiomyopathy,

and insufficiency of the mitral and tricuspid valves.

Pulmonary disease affects up to 50% of those

patients. Pulmonary infiltrates and fibrosis may

develop focal or diffuse. Hematologic

manifestations are largely nonspecific and may

include fatigue, which may be due to the anemia.

Thrombotic episodes due to cardiac injury or caused

by hypercoagulability occur frequently and often

present as neurologic symptoms. CNS dysfunction,

peripheral neuropathy, GI disorders and skin lesions

are also frequent manifestations (Gotlib 2015, Gotlib

2017).


Mohamed AN


Cytology

The most remarkable feature in the peripheral blood

is hypereosinophilia usually greater than 1.5x10 9 /L.

The leukocyte count is often moderately elevated

between 20,000-30,000/μL, and eosinophils in most

instances account for 30%-70% of the differential

counts. The blood exhibits mature eosinophils with

only a small number of eosinophilic myelocytes or

promyelocytes. A range of eosinophil abnormalities

may be seen such as sparse granulation, cytoplasmic

vaculation, small or immature granules, nuclear

hypersegmentation or hyposegmentation. Some

patients may show monocytosis, mild basophillia or

increased blasts. Anemia and thrombocytopenia may

be present (Gotlib, 2017).

The bone marrow is usually hypercellular and shows

eosinophilic hyperplasia. Eosinophil counts may

range from 10% -70% of the bone marrow nucleated

cells, with an average of 30%. The maturation of

eosinophils and myeloid cells is progressive but

often left-shifted with increased blasts (5%-19%).

Charcot-Leyden crystals are frequently seen which

are colorless crystals formed from the breakdown of

eosinophils. Eosinophils may show dysplastic

changes such as nuclear hypersegmentation or

hyposegmentation, cytoplasmic vacuolization or

hypogranularity, and/or abnormal eosinophilic

granules. Still, these morphologic changes and

Charcot-Leyden crystals are not specific for CEL

since may be seen in reactive eosinophilia. Marrow

fibrosis is seen in some cases (Bain et al, 2016).

Eosinophilic infiltration may also be present in

extramedullary tissues, most frequently involving

skin, heart, lung, nervous system and gastrointestinal

(GI) tract. Organ damage induced by eosinophilic

infiltration is due to the release of eosinophil

granules which contain toxic cationic proteins, the

primary mediators of tissue damage. The site of

infiltration usually shows some degree of fibrosis,

often with the presence of Charcot-Leyden crystals.

Cytogenetics

Both CEL-NOS and idiopathic HES require the

exclusion of the genetically defined eosinophilic

neoplasms specifically cases with rearrangements of

PDGFRA, PDGFRB, FGFR1, PCM1/JAK2 or

variants [Figure 1]. In rare cases, the finding of Ph

chromosome/BCR-ABL fusion indicates CML with

dominant eosinophilia. No specific cytogenetic

abnormality has been identified in CEL-NOS.

Nevertheless, chromosomal abnormalities

associated myeloid neoplasms such as trisomy

chromosome 8, deletion of chromosome 7/7q,

isochromosome 17q, and complex karyotype are

frequently observed which indicate clonality and

support the diagnosis of CEL-NOS. Humara test, X-

linked polymorphism, has been used in female

patients to demonstrate clonality.

Treatment

Various agents are often used sequentially over the

course of disease for treatment of CEL-NOS and

idiopathic HES. Corticosteroid is the first-line

therapy that induces remission in over 80% of

patients. Hydroxyurea, and interferon alpha are also

effective but are limited by their toxicity (Ogbogu et

al, 2009). Alemtuzumab, an anti-CD52 monoclonal

antibody, has been shown to control symptoms as

well as eosinophilia in patients with refractory

hypereosinophilic syndrome. Response to tyrosine

kinase inhibitors, such as Imatinib is uncommon.

High dose chemotherapy has been in used in some

patients when disease showed progression. For

those patients who fail the available pharmacologic

therapies, stem cell transplant offers the potential for

long-term remission and possible cure. In addition,

patients may require interventions for specific

cardiac complications, such as valve replacement,

endomyocardectomy or thrombectomy. Evidence of

hypersplenism and pain due to splenic infarction are

indications for splenectomy (Gotlib, 2015).

Prognosis

CEL-NOS is a clinically aggressive disease, with a

high rate transformation to acute leukemia, resistant

to conventional therapy, and short survival. In a

small series of 10 patients with CEL-NOS, the

median survival time was little over 22 months with

50% of patients transformed to acute leukemia

(Helbig et al 2012). Splenomegaly, increased blasts

in bone marrow, cytogenetic abnormalities and

dysplastic features of myeloid lineage are

unfavorable prognostic findings. However,

idiopathic HES is more heterogeneous and the

median survival is longer than that of CEL-NOS

(Wang et al, 2016). Features that signify a better

prognosis include the absence of cardiac or

neurologic involvement, lower eosinophil counts,

and steroid-responsiveness.

Genetics

Note

Mutations in the JAK2, ASXL1, TET2, and EZH2

genes are frequently seen in CEL-NOS cases.

Recently, Anderson and colleagues isolated

eosinophils and performed next generation whole

genome sequencing in five patients with idiopathic

HES. Somatic missense mutations were found in

three patients, including spliceosome gene PUF60

and the cadherin gene CDH17. In addition, they

showed that aberrant DNA methylation patterns can

distinguish clonal from reactive eosinophilia, which

may be very useful in daily clinical work (Andersen

et al, 2015). Other study used targeted next-

generation sequencing panels designed for myeloid

neoplasms to bone marrow specimens from a cohort

of 51 idiopathic HES patients and 17 CEL-NOS


Mohamed AN


patients (Wang et al, 2016). Mutations were detected

in 14/51 (28%) of idiopathic HES involving single

gene in 7 and ≥ 2 in the other 7 patients. Mutations

frequently affected genes involving DNA

methylation and chromatin modification. The more

frequently mutated genes included ASXL1, TET2,

EZH2, SETBP1, CBL, and NOTCH1. Mutations

that characterize classic myeloproliferative

neoplasms, including JAK2 V617F, MPL, and

CALR, were all negative. KIT mutations were also

not detected in any of their cases. The other 17 CEL-

NOS showed multiple mutations, involving ASXL1,

CSF3R, SETBP1, U2AF1, EZH2 and ETV6.

However somatic mutations in genes such as TET2,

JAK2, ASXL2, TP53 and others have been

frequently found in elderly healthy individuals,

therefore, these mutations should be interpreted with

caution. Moreover, idiopathic HES patients with

mutations, as a group, showed a number of clinical,

laboratory and bone marrow findings resembling

CEL-NOS. Wang and Colleagues concluded that

targeted next-generation sequencing helps to

establish clonality in a subset of patients with

hypereosinophilia that would otherwise be classified

as idiopathic hypereosinophilic syndrome (Wang et

al 2016).

References Andersen CL, Nielsen HM, Kristensen LS, Søgaard A, Vikeså J, Jønson L, Nielsen FC, Hasselbalch H, Bjerrum OW, Punj V, Grønbæk K. Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome. Oncotarget. 2015 Dec 1;6(38):40588-97

Bain BJ. Eosinophilic leukemia and idiopathic hypereosinophilic syndrome are mutually exclusive diagnoses. Blood. 2004 Dec 1;104(12):3836; author reply 3836-7

Bain BJ, Gilliland DG, Horny H-P, Hasserjian RP, Orazi A. Chronic eosinophilic leukaemia, not otherwise specified.

Swerdlow S, Harris NL, Stein H, Jaffe ES, Theile J, Vardiman JW, eds.

Crane MM, Chang CM, Kobayashi MG, Weller PF. Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence J Allergy Clin Immunol 2010 Jul;126(1):179-81

Gotlib J. World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management Am J Hematol 2017 Nov;92(11):1243-1259

Gotlib J, Cools J. Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias Leukemia 2008 Nov;22(11):1999-2010

Helbig G, Soja A, Bartkowska-Chrobok A, Kyrcz-Krzemie&nacute; S. Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation Am J Hematol 2012 Jun;87(6):643-5

Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, Leiferman KM, Nutman TB, Pfab F, Ring J, Rothenberg ME, Roufosse F, Sajous MH, Sheikh J, Simon D, Simon HU, Stein ML, Wardlaw A, Weller PF, Klion AD. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy J Allergy Clin Immunol 2009 Dec;124(6):1319-25

Tefferi A, Patnaik MM, Pardanani A. Eosinophilia: secondary, clonal and idiopathic Br J Haematol 2006 Jun;133(5):468-92

Wang SA, Tam W, Tsai AG, Arber DA, Hasserjian RP, Geyer JT, George TI, Czuchlewski DR, Foucar K, Rogers HJ, Hsi ED, Bryan Rea B, Bagg A, Dal Cin P, Zhao C, Kelley TW, Verstovsek S, Bueso-Ramos C, Orazi A. Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified Mod Pathol 2016 Aug;29(8):854-64


Mohamed AN. Chronic Eosinophilic Leukemia-Not Otherwise Specified (CEL-NOS) - Idiopathic Hypereosinophilic Syndrome (IHES). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(3):72-75.




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