Abstract
Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts, 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P=0.0004; hazard ration 4.0, 95% confidence interval 1.9–8.8), revised International Prognostic Scoring System risk category (P<0.0001), and red cell transfusion need (P=0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P=0.001; hazard ration 7.0, 95% confidence interval 2.3–20.8). The presence of IDH2R140Q did not affect the overall (P=0.54) or leukemia-free (P=0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.
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References
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–1812.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.
Chou WC, Lei WC, Ko BS, Hou HA, Chen CY, Tang JL et al. The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 2011; 25: 246–253.
Boissel N, Nibourel O, Renneville A, Gardin C, Reman O, Contentin N et al. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol 2010; 28: 3717–3723.
Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood 2010; 116: 2122–2126.
Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M et al. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 2010; 95: 1668–1674.
Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 2010; 24: 1094–1096.
Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 2010; 24: 1302–1309.
Pardanani A, Patnaik MM, Lasho TL, Mai M, Knudson RA, Finke C et al. Recurrent IDH mutations in high-risk myelodysplastic syndrome or acute myeloid leukemia with isolated del(5q). Leukemia 2010; 24: 1370–1372.
Soverini S, Score J, Iacobucci I, Poerio A, Lonetti A, Gnani A et al. IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis. Leukemia 2011; 25: 178–181.
Caramazza D, Lasho TL, Finke CM, Gangat N, Dingli D, Knudson RA et al. IDH mutations and trisomy 8 in myelodysplastic syndromes and acute myeloid leukemia. Leukemia 2010; 24: 2120–2122.
Green CL, Evans CM, Hills RK, Burnett AK, Linch DC, Gale RE . The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood 2010; 116: 2779–2782.
Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T . IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood 2010; 116: 5486–5496.
Thol F, Damm F, Wagner K, Gohring G, Schlegelberger B, Hoelzer D et al. Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 2010; 116: 614–616.
Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 2010; 28: 3636–3643.
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010; 28: 2348–2355.
Wagner K, Damm F, Gohring G, Gorlich K, Heuser M, Schafer I et al. Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol 2010; 28: 2356–2364.
Green CL, Evans CM, Zhao L, Hills RK, Burnett AK, Linch DC et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood 2011; 118: 409–412.
Tefferi A, Jimma T, Sulai NH, Lasho TL, Finke CM, Knudson RA et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia 2011; e-pub ahead of print 13 September 2011; doi:10.1038/leu.2011.253.
Greenberg P, Tuechler J, Schanz J, Sole F, Bennet JM, Garcia-Manero G et al. Revised international prognostic scoring system (IPSS-R), developed by the international prognostic working group for prognosis in MDS (IWG-PM). Leuk Res 2011; 35: S6.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. 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.
Tefferi A, Lasho TL, Huang J, Finke C, Mesa RA, Li CY et al. Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia 2008; 22: 756–761.
Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.
Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009; 23: 900–904.
Tefferi A, Lasho TL, Patnaik MM, Finke CM, Hussein K, Hogan WJ et al. JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival. Leukemia 2010; 24: 105–109.
Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 2009; 324: 261–265.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462: 739–744.
Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 2010; 207: 339–344.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17: 225–234.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation. Cancer Cell 2010; 18: 553–567.
Patnaik MM, Lasho TL, Finke CM, Knudson RA, Ketterling RP, Chen D et al. Isolated del(5q) in myeloid malignancies: clinicopathologic and molecular features in 143 consecutive patients. Am J Hematol 2011; 86: 393–398.
Acknowledgements
The current study is supported in part by grants from the ‘Myeloproliferative Disorders Foundation, Chicago, IL, USA’ and ‘The Henry J Predolin Foundation for Research in Leukemia, Mayo Clinic, Rochester, MN, USA’.
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Patnaik, M., Hanson, C., Hodnefield, J. et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic Study of 277 patients. Leukemia 26, 101–105 (2012). https://doi.org/10.1038/leu.2011.298
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DOI: https://doi.org/10.1038/leu.2011.298
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