Abstract
Mutations in the TET2 and ASXL1 genes have been described in approximately 14% and 8% of patients, respectively, with classic myeloproliferative neoplasms (MPN), but their role as possible new diagnostic molecular markers is still inconclusive. In addition, other genes such as IDH1, IDH2, and c-CBL have also been reported in several myeloid neoplasms. We have studied the mutational status of TET2 (complete coding region), ASXL1 (exon12), IDH1 (R132), IDH2 (R140 and R172), and c-CBL (exons 8 and 9) in 62 MPN patients (52 essential thrombocythemia (ET), five polycythemia vera (PV), and five primary myelofibrosis (PMF)) negative for both JAK2 (V617F and exon 12) and MPL (exon 10) mutations. Pathogenic alterations in the TET2 gene were detected in three out 52 ET cases (4.8%). ASXL1 gene pathogenic mutations were also detected in three cases (two ET and one PMF). One ET patient harbored, simultaneously, one TET2 and one ASXL1 mutations. Mutations in the TET2 and ASXL1 genes showed no association with the JAK2 46/1 haplotype. Analysis of a JAK2V617F-positive cohort of 50 ET patients showed no mutations in either the TET2 or ASXL1 genes. Regarding IDH1, IDH2, and c-CBL genes, no mutations were found in any patient. In conclusion, TET2 and ASXL1 pathogenic mutations are found in 8% of MPN lacking JAK2 and MPL mutations, whereas IDH1, IDH2, and c-CBL mutations are not detected in this subset of patients.
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Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, PatelJ WM et al (2009) Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:144–147
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S et al (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301
Couronné L, Lippert E, Andrieux J, Kosmider O, Radford-Weiss I, Penther D et al (2009) Analyses of TET2 mutations in post-myeloproliferative neoplasm acute myeloid leukemias. Leukemia 24:201–203
Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M et al (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842
Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J et al (2009) TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 23:905–911
Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J et al (2009) Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 23:900–904
Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM et al (2009) Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia 23:1343–1345
Abdel-Wahab (2011) Genetics of the myeloproliferative neoplasms. Curr Opin Hematol 18:117–123
Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adélaïde J, Rey J et al (2009) Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23:2183–2186
Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N et al (2009) Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematology 145:788–800
Abdel-Wahab O, Pardanani A, Patel J, Lasho T, Heguy A, Levine RL et al (2010) Concomitant analysis of EZH2 and ASXL1 Mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Blood (ASH Annual Meeting Abstracts) 116:1267, Abstr. 3070
Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay KO et al (2010) Distinct clinical and biological characteristics in adult acute myeloid leukemia bearing isocitrate dehydrogenase 1 (IDH1) mutation. Blood 115:2749–2754
Mardis ET, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al (2009) Recurring mutations found by sequencing and acute myeloid leukemia genome. N Engl J Med 361:1058–1066
Green A, Beer P (2010) Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med 362:369–370
Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, Tefferi A (2010) IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia 24:1146–1151
Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D et al (2010) IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 24:1302–1309
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234
Sargin B, Choudhary C, Crosetto N, Schmidt MH, Grundler R, Rensinghoff M et al (2007) Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110:1004–1012
Dunbar AJ, Gondek LP, O’Keefe CL, Makishima H, Rataul MS, Szpurka H et al (2008) 250 K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res 68:10349–10357
Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C et al (2009) Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 113:6182–6192
Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S et al (2009) Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114:1859–1863
Reindl C, Quentmeier H, Petropoulos K, Greif PA, Benthaus T, Argiropoulos B et al (2009) CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin Cancer Res 215:2238–2247
Jones AV, Chase A, Silver RT, Oscier D, Zoi K, Wang YL et al (2009) JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 41:446–449
Kilpivaara O, Mukherjee S, Schram AM, Wadleigh M, Mullally A, Ebert BL et al (2009) A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet 41:455–459
Olcaydu D, Harutyunyan A, Jäger R, Berg T, Gisslinger B, Pabingir I et al (2009) A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41:450–454
Olcaydu D, Skoda RC, Looser R, Li S, Cazzola M, Pietra D et al (2009) The ´GGCC´haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera. Leukemia 23:1924–1926
Jones AV, Campbell PJ, Beer PA, Schnittger S, Vannucchi AM, Zoi K et al (2010) The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms. Blood 115:4517–4523
Beer PA, Delhommeau F, LeCouédic JP, Dawson MA, Chen E, Bareford D et al (2009) Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood 115:2891–2900
Abdel-Wahab O, Manshouri T, Patel J (2010) Genetic analysis of transforming events that convert chronic myeloproliferative neoplasm to leukemias. Canc Res 70:447–452
Schaub FX, Looser R, Li S, Hao-Shen H, Lehmann T, Tichelli A, Skoda RC (2010) Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Blood 115:2003–2007
Kosmider O, Delabesse, Mansat-De Mas V, Cornillet-Lefebvre P, Blanchet O, Delmer A et al (2011) TET2 mutations in secondary acute myeloid leukemias: a French retrospective study. Haematologica 96:1059–1063
Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B et al (2010) Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol 28:3858–3865
Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Gäken J, Lea NC, Przychodzen B et al (2010) Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood 116:3923–3932
Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G et al (2011) TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 29:1971–1979
Acknowledgments
This work was supported by grants from the Spanish Health Ministry “Fondo de Investigación Sanitaria” EC 07/90791, PI10/01807, Instituto de Salud Carlos III FEDER (RD09/0076/00036), and the “Xarxa de Bancs de Tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC)”. Luz Martínez-Avilés is recipient of a fellowship from the “Comissionat per a Universitats i Recerca del department d’ Innovació, Universitats i Empresa de la Generalitat de Catalunya i del Fons Social Europeu.”
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Martínez-Avilés, L., Besses, C., Álvarez-Larrán, A. et al. TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Ann Hematol 91, 533–541 (2012). https://doi.org/10.1007/s00277-011-1330-0
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DOI: https://doi.org/10.1007/s00277-011-1330-0