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BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1genes

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

Chronic myelomonocytic leukemia (CMML) is a hematological disease close to, but separate from both myeloproliferative disorders (MPD) and myelodysplastic syndromes and may show either myeloproliferative (MP-CMML) or myelodysplastic (MD-CMML) features. Not much is known about the molecular biology of this disease.

Methods

We studied a series of 30 CMML samples (13 MP- and 11 MD-CMMLs, and 6 acutely transformed cases) from 29 patients by using Agilent high density array-comparative genomic hybridization (aCGH) and sequencing of 12 candidate genes.

Results

Two-thirds of samples did not show any obvious alteration of aCGH profiles. In one-third we observed chromosome abnormalities (e.g. trisomy 8, del20q) and gain or loss of genes (e.g. NF1, RB1 and CDK6). RAS mutations were detected in 4 cases (including an uncommon codon 146 mutation in KRAS) and PTPN11 mutations in 3 cases. We detected 11 RUNX1 alterations (9 mutations and 2 rearrangements). The rearrangements were a new, cryptic inversion of chromosomal region 21q21-22 leading to break and fusion of RUNX1 to USP16. RAS and RUNX1 alterations were not mutually exclusive. RAS pathway mutations occurred in MP-CMMLs (~46%) but not in MD-CMMLs. RUNX1 alterations (mutations and cryptic rearrangement) occurred in both MP and MD classes (~38%).

Conclusion

We detected RAS pathway mutations and RUNX1 alterations. The latter included a new cryptic USP16-RUNX1 fusion. In some samples, two alterations coexisted already at this early chronic stage.
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Literature
1.
Vardiman JW, Harris NL, Brunning RD: The world health classification (WHO) of myeloid neoplasms. Blood. 2002, 100: 2292-2302. 10.1182/blood-2002-04-1199.CrossRefPubMed
2.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, Sultan C, Cox C: The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol. 1994, 84: 746-754. 10.1111/j.1365-2141.1994.tb06734.x.CrossRef
3.
Germing U, Gattermann N, Minning H, Heyll A, Aul C: Problems in the classification of CMML–dysplastic versus proliferative type. Leuk Res. 1998, 22: 871-878. 10.1016/S0145-2126(97)00192-6.CrossRefPubMed
4.
Nosslinger T, Reisner R, Grüner H, Tüchler H, Nowotny H, Pittermann E, Pfeilstöcker M: Dysplastic versus proliferative CMML–a retrospective analysis of 91 patients from a single institution. Leuk Res. 2001, 25: 741-747. 10.1016/S0145-2126(01)00014-5.CrossRefPubMed
5.
Gonzalez-Medina IBJ, Torrequebrada A, Lopez A, Vallespi T, Massague I: Two groups of chronic myelomonocytic leukaemia: myelodysplastic and myeloproliferative. Prognostic implications in a series of a single center. Leuk Res. 2002, 26: 821-824. 10.1016/S0145-2126(02)00021-8.CrossRefPubMed
6.
Onida F: Pronostics factors in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002, 99: 840-849. 10.1182/blood.V99.3.840.CrossRefPubMed
7.
Germing U, Strupp C, Knipp S, Kuendgen A, Giagounidis A, Hildebrandt B, Aul C, Haas R, Gattermann N, bennett JM: Chronic myelomonocytic leukemia in the light of the WHO proposals. Haematologica. 2007, 92: 974-977. 10.3324/haematol.11051.CrossRefPubMed
8.
Gelsi-Boyer V, Cervera N, Bertucci F, Trouplin V, Remy V, Olschwang S, Chaffanet M, Vey N, Mozziconacci MJ, Birnbaum D: Gene expression profiling separates chronic myelomonocytic leukemia in two molecular subtypes. Leukemia. 2007, 21: 2359-2362. 10.1038/sj.leu.2404805.CrossRefPubMed
9.
Etienne A, Carbuccia N, Adélaide J, Bekhouche I, Rémy V, Sohn C, Sainty D, Gastaut JA, Olschwang S, Birnbaum D, Mozziconacci MJ, Chaffanet M: Rearrangements involving 12q in myeloproliferative disorders: possible role of HMGA2 and SOCS2 genes. Cancer Genet Cytogenet. 2007, 176: 80-88. 10.1016/j.cancergencyto.2007.03.009.CrossRefPubMed
10.
Adélaide J, Finetti P, Bekhouche I, Repellini L, Geneix J, Sircoulomb F, Charafe-Jauffret E, Cervera N, Desplans J, Parzy D, Schoenmakers E, Viens P, Jacquemier J, Birnbaum D, Bertucci F, Chaffanet M: Integrated profiling of basal and luminal breast cancers. Cancer Res. 2007, 67: 11565-11575. 10.1158/0008-5472.CAN-07-2536.CrossRefPubMed
11.
Barrett MT, Scheffer A, Ben-Dor A, Sampas N, Lipson D, Kincaid R, Tsang P, Curry B, Baird K, Meltzer PS, Yakhini Z, Bruhn L, Laderman S: Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc Natl Acad Sci USA. 2004, 101: 17765-17770. 10.1073/pnas.0407979101.CrossRefPubMedPubMedCentral
12.
Murati A, Adélaide J, Popovici C, Mozziconacci MJ, Arnoulet C, Lafage-Pochitaloff M, Sainty D, Birnbaum D, Chaffanet M: A further case of acute myelomonocytic leukemia with inv(8) chromosomal rearrangement and MOZ-NCOA2 gene fusion. Int J Mol Med. 2003, 12: 423-428.PubMed
13.
Edkins S, O'Meara S, Parker A, Stevens C, Reis M, Jones S, Greenman C, Davies H, Dalgliesh G, Forbes S, Hunter C, Smith R, Stephens P, Goldstraw P, Nicholson A, Chan TL, Velculescu VE, Yuen ST, Leung SY, Stratton MR, Futreal PA: Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006, 5: 928-932.CrossRefPubMedPubMedCentral
14.
Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD: Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007, 39: 1007-1012. 10.1038/ng2073.CrossRefPubMed
15.
Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R: Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007, 39: 1013-1017. 10.1038/ng2078.CrossRefPubMed
16.
Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS: Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007, 39: 70-74. 10.1038/ng1926.CrossRefPubMed
17.
Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E: Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007, 39: 1120-1126. 10.1038/ng2113.CrossRefPubMed
18.
Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N, Kaneko Y, Ohki M: The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood. 1997, 89: 3936-3944.PubMed
19.
Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K: A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood. 2000, 96: 3209-3214.PubMed
20.
Tartaglia L, Gelb BD: Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005, 6: 45-68. 10.1146/annurev.genom.6.080604.162305.CrossRefPubMed
21.
Ferner RE: Neurofibromatosis 1. Eur J Human Genet. 2007, 15: 131-138. 10.1038/sj.ejhg.5201676.CrossRef
22.
Lauchle JO, Braun BS, Loh ML, Shannon K: Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatr Blood Cancer. 2006, 46: 579-585. 10.1002/pbc.20644.CrossRefPubMed
23.
Schubbert S, Shannon K, Bollag G: Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007, 4: 295-308. 10.1038/nrc2109.CrossRef
24.
Bentires-Alj M, Kontaridis M, Neel BG: Stops along the RAS pathway in human genetic disease. Nat Med. 2006, 12: 283-285. 10.1038/nm0306-283.CrossRefPubMed
25.
Tyner JW, Loriaux MM, Erickson H, Eide CA, Deininger J, Macpartlin M, Willis SG, Lange T, Druker BJ, Kovacsovics T, Maziarz R, Gattermann N, Deininger MW: High-throughput mutational screen of the tyrosine kinome in chronic myelomonocytic leukemia. Leukemia. 2008
26.
Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG: Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004, 15: 8816-8820. 10.1158/0008-5472.CAN-04-1923.CrossRef
27.
Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, Mercer KL, Grochow R, Hock H, Crowley D, Hingorani SR, Zaks T, King C, Jacobetz MA, Wang L, Bronson RT, Orkin SH, DePinho RA, Jacks T: Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004, 5: 375-387. 10.1016/S1535-6108(04)00085-6.CrossRefPubMed
28.
Braun BS, Tuveson D, Kong N, Le DT, Rozmus J, Le Beau MM, Jacks TE, Shannon KM: Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA. 2004, 101: 597-602. 10.1073/pnas.0307203101.CrossRefPubMed
29.
Chan IT, Kutok J, Williams IR, Cohen S, Kelly L, Shigematsu H, Johnson L, Akashi K, Tuveson DA, Jacks T, Gilliland DG: Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Clin Invest. 2004, 113: 528-538.CrossRefPubMedPubMedCentral
30.
Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergsträsser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M, Loh ML: The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005, 106: 2183-2185. 10.1182/blood-2005-02-0531.CrossRefPubMedPubMedCentral
31.
Loh ML, Martinelli S, Cordeddu V, Reynolds MG, Vattikuti S, Lee CM, Wulfert M, Germing U, Haas P, Niemeyer C, Beran ME, Strom S, Lübbert M, Sorcini M, Estey EH, Gattermann N, Tartaglia M: Acquired PTPN11 mutations occur rarely in adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Res. 2005, 29: 459-462. 10.1016/j.leukres.2004.10.001.CrossRefPubMed
32.
Morerio C, Acquila M, Rosanda C, Rapella A, Dufour C, Locatelli F, Maserati E, Pasquali F, Panarello C: HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic leukemia with t(5;17)(q33;p11.2). Cancer Res. 2004, 64: 2649-2651. 10.1158/0008-5472.CAN-03-4026.CrossRefPubMed
33.
Flotho C, Kratz C, Niemeyer CM: Targeting RAS signaling pathways in juvenile myelomonocytic leukemia. Curr Drug Targets. 2007, 8: 715-725. 10.2174/138945007780830773.CrossRefPubMed
34.
Flotho C, Steinemann D, Mullighan CG, Neale G, Mayer K, Kratz CP, Schlegelberger B, Downing JR, Niemeyer CM: Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11. Oncogene. 2007, 26: 5816-5821. 10.1038/sj.onc.1210361.CrossRefPubMed
35.
Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG: Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999, 23: 166-175. 10.1038/13793.CrossRefPubMed
36.
Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K, Ogawa S, Chiba S, Mitani K, Hirai H: Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood. 2000, 96: 3154-3160.PubMed
37.
Niebuhr B, Fischer M, Tager M, Cammenga J, Stocking C: Gatekeeper function of the RUNX1 transcription factor in acute leukemia. Blood Cells Mol Dis. 2008, 40: 211-218. 10.1016/j.bcmd.2007.07.018.CrossRefPubMed
38.
Mitelman F, Johansson B, Mertens F: The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007, 7: 233-245. 10.1038/nrc2091.CrossRefPubMed
39.
Kurokawa M: AML1/Runx1 as a versatile regulator of hematopoiesis: regulation of its function and a role in adult hematopoiesis. Int J Hematol. 2006, 84: 136-142. 10.1532/IJH97.06070.CrossRefPubMed
40.
Osato M: Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene. 2004, 23: 4284-4296. 10.1038/sj.onc.1207779.CrossRefPubMed
41.
Liu H, Holm M, Xie XQ, Wolf-Watz M, Grundstrom T: AML1/Runx1 recruits calcineurin to regulate granulocyte macrophage colony-stimulating factor by Ets1 activation. J Biol Chem. 2004, 279: 29398-29408. 10.1074/jbc.M403173200.CrossRefPubMed
42.
Fujimoto T, Anderson K, Jacobsen SE, Nishikawa SI, Nerlov C: Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007, 26: 2361-2370. 10.1038/sj.emboj.7601675.CrossRefPubMedPubMedCentral
43.
Nagel S, Leich E, Quentmeier H, Meyer C, Kaufmann M, Drexler HG, Zettl A, Rosenwald A, MacLeod RA: Amplification at 7q22 targets cyclin-dependent kinase 6 in T-cell lymphoma. Leukemia. 2008, 22: 387-392. 10.1038/sj.leu.2405028.CrossRefPubMed
44.
Xinh PT, Tri NK, Nagao H, Nakazato H, Taketazu F, Fujisawa S, Yagasaki F, Chen YZ, Hayashi Y, Toyoda A, Hattori M, Sakaki Y, Tokunaga K, Sato Y: Breakpoints at 1p36.3 in three MDS/AML(M4) patients with t(1;3)(p36;q21) occur in the first intron and in the 5' region of MEL1. Genes Chromosomes Cancer. 2003, 36: 313-316. 10.1002/gcc.10176.CrossRefPubMed
45.
Christiansen DH, Desta F, Andersen MK, Pedersen-Bjergaard J: Mutations of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations. Genes Chromosome Cancer. 2007, 46: 517-521. 10.1002/gcc.20426.CrossRef
Metadata
Title
Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1genes
Publication date
01-12-2008
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-299

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