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BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias

Authors: Julien Rocquain, Nadine Carbuccia, Virginie Trouplin, Stéphane Raynaud, Anne Murati, Meyer Nezri, Zoulika Tadrist, Sylviane Olschwang, Norbert Vey, Daniel Birnbaum, Véronique Gelsi-Boyer, Marie-Joelle Mozziconacci

Published in: BMC Cancer | Issue 1/2010

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Abstract

Background

Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation.

Methods

We searched for mutations in the ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype.

Results

Mutations in ASXL1 and CBL were frequent in refractory anemia with excess of blasts. Mutations in TET2 occurred with similar frequency in MDSs and AMLs and associated equally with either ASXL1 or NPM1 mutations. Mutations of RUNX1 were mutually exclusive with TET2 and combined with ASXL1 but not with NPM1. Mutations in FLT3 (mutation and internal tandem duplication), IDH1, IDH2, NPM1 and WT1 occurred primarily in AMLs.

Conclusion

Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.
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Literature
1.
Tefferi A, Vardiman JW: Myelodysplastic syndromes. N Eng J Med. 2009, 361: 1872-1885. 10.1056/NEJMra0902908.CrossRef
2.
Acquaviva C, Gelsi-Boyer V, Birnbaum D: Myelodysplastic syndromes: lost between two states?. Leukemia. 2010, 24: 1-5. 10.1038/leu.2009.157.CrossRefPubMed
3.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Bernard OA: Mutation in TET2 in myeloid cancers. N Engl J Med. 2009, 360: 2289-2301. 10.1056/NEJMoa0810069.CrossRefPubMed
4.
Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL: Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia. 2009, 23: 1343-1345. 10.1038/leu.2009.59.CrossRefPubMedPubMedCentral
5.
Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, O'Keefe CL, Ganetzky R, McDevitt MA, Maciejewski JP: Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009, 113: 6403-6410. 10.1182/blood-2009-02-205690.CrossRefPubMedPubMedCentral
6.
Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao JJ, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL: Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009, 114: 144-147. 10.1182/blood-2009-03-210039.CrossRefPubMedPubMedCentral
7.
Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, Geurts van Kessel A, Raymakers RAP, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Janssen JH: Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009, 41: 838-842. 10.1038/ng.391.CrossRefPubMed
8.
Mohamedali AM, Smith AE, Gaken J, Lea NC, Mian SA, Westwood NB, Strupp C, Gattermann N, Germing U, Mufti GJ: Novel TET2 mutations associated with UPD4q24 in myelodysplastic syndromes. J Clin Oncol. 2009, 27: 4002-4006. 10.1200/JCO.2009.22.6985.CrossRefPubMed
9.
Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F, Viguié F, Quesnel B, Beyne-Rauzy O, Solary E, Vey N, Hunault-Berger M, Fenaux P, Mansat-De Mas V, Delabesse E, Guardiola P, Lacombe C, Vainchenker W, Preudhomme C, Dreyfus F, Bernard OA, Birnbaum D, Fontenay M: TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDS). Blood. 2009, 114: 3285-3291. 10.1182/blood-2009-04-215814.CrossRefPubMed
10.
Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N, Lagarde A, Prébet T, Nezri M, Sainty D, Olschwang S, Xerri L, Chaffanet M, Mozziconacci MJ, Vey N, Birnbaum D: Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009, 145: 788-800. 10.1111/j.1365-2141.2009.07697.x.CrossRefPubMed
11.
Makishima H, Cazzolli H, Szpurka H, Dunbar A, Tiu R, Huh J, Muramatsu H, O'Keefe C, Hsi E, Paquette RL, Kojima S, List AF, Sekeres MA, McDevitt MA, Maciejewski JP: Mutations of E3 ligase Cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J Clin Oncol. 2009, 27: 6109-6116. 10.1200/JCO.2009.23.7503.CrossRefPubMedPubMedCentral
12.
Falini B, Bolli N, Liso A, Martelli MP, Mannucci R, Pileri S, Nicoletti N: Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia. 2009, 23: 1731-1743. 10.1038/leu.2009.124.CrossRefPubMed
13.
Gaidzik V, Döhner K: Prognostic implications of gene mutations in acute myeloid leukemia with normal karyotype. Semin Oncol. 2008, 35: 346-355. 10.1053/j.seminoncol.2008.04.005.CrossRefPubMed
14.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Elred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, Ley TJ: Recurrent mutations found by sequencing an acute myeloid leukemia genome. N Eng J Med. 2009, 361: 1058-1066. 10.1056/NEJMoa0903840.CrossRef
15.
Carbuccia N, Trouplin V, Gelsi-Boyer V, Murati A, Rocquain J, Adélaïde J, Olschwang S, Xerri L, Vey N, Chaffanet M, Birnbaum D, Mozziconacci MJ: Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias. Leukemia. 2010, 24: 469-473. 10.1038/leu.2009.218.CrossRefPubMed
16.
Gilliland DG: Molecular genetics of human leukemias: new insights into therapy. Semin Hematol. 2002, 39: 6-11. 10.1053/shem.2002.36921.CrossRefPubMed
17.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009, 114: 937-951. 10.1182/blood-2009-03-209262.CrossRefPubMed
18.
Murati A, Gervais C, Carbuccia N, Finetti P, Cervera N, Adélaïde J, Struski S, Lippert E, Mugneret F, Tigaud I, Penther D, Bastard C, Poppe B, Speleman F, Baranger L, Luquet I, Cornillet-Lefebvre P, Nadal N, Nguyen-Khac F, Pérot C, Olschwang S, Bertucci F, Chaffanet M, Lessard M, Mozziconacci MJ, Birnbaum D: Genomic profiling of acute myelomonocytic leukemia: alteration of the MYB locusin MYST3-linked cases. Leukemia. 2009, 23: 85-94. 10.1038/leu.2008.257.CrossRefPubMed
19.
Gelsi-Boyer V, Trouplin V, Adélaïde J, Aceto N, Remy V, Pinson S, Houdayer C, Arnoulet C, Sainty D, Bentires-Alj M, Olschwang S, Vey N, Mozziconacci MJ, Birnbaum D, Chaffanet M: Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes. BMC Cancer. 2008, 8: 299-314. 10.1186/1471-2407-8-299.CrossRefPubMedPubMedCentral
20.
Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamasaki S, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K, Oda H, Yamagata T, Takita J, Gotoh N, Nakazaki K, Kawamata N, Onodera M, Nobuyoshi M, Hayashi Y, Harada H, Kurokawa M, Chiba S, Mori H, Ozawa K, Omine M, Hirai H, Nakauchi H, Koeffler HP, Ogawa S: Gain-of-function of mutated CBL tumour suppressor in myeloid neoplasms. Nature. 2009, 460: 904-908. 10.1038/nature08240.CrossRefPubMed
21.
Renneville A, Boissel N, Zurawski V, Llopis L, Biggio V, Nibourel O, Philippe N, Thomas X, Dombret H, Preudhomme C: Wilms tumor gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer. 2009, 115: 3719-3727. 10.1002/cncr.24442.CrossRefPubMed
22.
Virappane P, Gale R, Hills R, Kakkas I, Summers K, Stevens J, Allen C, Green C, Quentmeier H, Drexler H, Burnett A, Linch D, Bonnet D, Lister TA, Fitzgibbon J: Mutation of the Wilm's tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukaemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol. 2008, 26: 5429-5435. 10.1200/JCO.2008.16.0333.CrossRefPubMed
23.
Green A, Beer P: Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. New Engl J Med. 2010, 362: 369-370. 10.1056/NEJMc0910063.CrossRefPubMed
24.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett B, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su S, Sharp KA, Levine RL, Thompson CB: The common features of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydoxyglutarate. Cancer Cell. 2010, 17: 1-10. 10.1016/j.ccr.2010.01.020.CrossRef
25.
Boultwood J, Perry J, Pellagatti A, Fernandez-Mercado M, Fernandez-Santamaria C, Calasanz MJ, Larrayoz MJ, Garcia-Delgado M, Giagounidis A, Malcovati L, Della Porta MG, Jädersten M, Killick S, Hellström-Lindbergh E, Cazzola M, Wainscoat JS: Frequent mutations of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia. 2010, 24: 1062-1065. 10.1038/leu.2010.20.CrossRefPubMed
26.
Lavagna-Sévenier C, Marchetto S, Birnbaum D, Rosnet O: FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Leukemia. 1998, 12: 301-310. 10.1038/sj.leu.2400921.CrossRefPubMed
27.
Dunbar AJ, Gondek LP, O'Keefe CL, Makishima H, Rataul MS, Szpurka H, Sekeres MA, Wang XF, McDevitt MA, Maciejewski JP: 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res. 2008, 68: 10340-10357. 10.1158/0008-5472.CAN-08-2754.CrossRef
28.
Pollard PJ, Ratcliffe PJ: Puzzling patterns of predisposition. Science. 2009, 324: 192-194. 10.1126/science.1173362.CrossRefPubMed
29.
Wagner KD, Wagner N, Wellman S, Schley G, Bondke A, Theres H, Scholz H: Oxygen-regulated expression of the Wilm's tumor suppressor Wt1 involves hypoxia-inducible factor-1 (HIF-1). FASEB J. 2003, 17: 1364-1366.PubMed
30.
Couronné L, Lippert E, Andrieux J, Kosmider O, Radford-Weiss I, Penther D, et al: Analyses of TET2 mutations in post-myeloproliferative neoplasm acute myeloid leukemias. Leukemia. 2010, 24: 201-203. 10.1038/leu.2009.169.CrossRefPubMed
31.
Bernard F, Gelsi-Boyer V, Murati A, Giraudier S, Trouplin V, Adélaïde J, Rey J, Olschwang S, Vainchenker W, Chaffanet M, Vey N, Mozziconacci MJ, Birnbaum D: Alterations of NFIA in chronic malignant myeloid diseases. Leukemia. 2009, 23: 583-585. 10.1038/leu.2008.228.CrossRefPubMed
32.
van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C, Edkins S, Hardy C, O'Meara S, Teague J, Butler A, Hinton J, Latimer C, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Cole J, Forbes S, Jia M, Jones D, Kok CY, Leroy C, Lin ML, McBride DJ, Maddison M, Maquire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, Pleasance E, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Collins VP, Ichimura K, Law S, Wong J, Yuen ST, Leung SY, Tonon G, DePinho RA, Tai YT, Anderson KC, Kahnoski RJ, Massie A, Khoo SK, Teh BT, Stratton MR, Futreal PA: Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 2009, 41: 521-523. 10.1038/ng.349.CrossRefPubMedPubMedCentral
33.
Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A, Drexler HG, Duncombe A, Cervantes F, Oscier D, Boultwood J, Grand FH, Cross NCP: Inactivating mutations of the histone methyltransferase gene EZH2in myeloid disorders. Nat Genet. 2010,
34.
Nikoloski G, Langemeijer SMC, Kuiper RP, Knops R, Massop M, Tönnissen ERLTM, van der Heijden A, Scheele TN, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH: Somatic mutations of the histone methyltransferase gene EZH2in myelodysplastic syndromes. Nat Genet. 2010,
35.
Ding Y, Harada Y, Imagawa J, Kimura A, Harada H: AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms. Blood. 2009, 114: 5201-5205. 10.1182/blood-2009-06-223982.CrossRefPubMed
36.
Abdel-Wahab O, Mansouri T, Patel J, Harris K, Yao J, Hedvat C, Hedvat C, Heguy A, Bueso-Ramos C, Kantarjian H, Levine RL, Verstovsek S: Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res. 2010, 70: 447-452. 10.1158/0008-5472.CAN-09-3783.CrossRefPubMedPubMedCentral
37.
Dang L, White DW, Gross S, Bennett BD, Bittinger MAA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009, 462: 739-744. 10.1038/nature08617.CrossRefPubMedPubMedCentral
38.
Grisendi S, Mecucci C, Falini B, Pandolfi PP: Nucleophosmin and cancer. Nat Rev Cancer. 2006, 494: 493-505. 10.1038/nrc1885.CrossRef
39.
Fisher CL, Pineault N, Brookes C, Helgason CD, Ohta H, Bodner C, Hess JL, Humphries RK, Brock HW: Loss-of-function Additional sex coombs-like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood. 2010, 115: 38-46. 10.1182/blood-2009-07-230698.CrossRefPubMedPubMedCentral
Metadata
Title
Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias
Authors
Julien Rocquain
Nadine Carbuccia
Virginie Trouplin
Stéphane Raynaud
Anne Murati
Meyer Nezri
Zoulika Tadrist
Sylviane Olschwang
Norbert Vey
Daniel Birnbaum
Véronique Gelsi-Boyer
Marie-Joelle Mozziconacci
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-401

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