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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2012

Open Access 01-12-2012 | Research

Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients

Authors: Sadudee Chotirat, Wanna Thongnoppakhun, Orathai Promsuwicha, Chetsada Boonthimat, Chirayu U Auewarakul

Published in: Journal of Hematology & Oncology | Issue 1/2012

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Abstract

Background

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to α-ketoglutarate. Acquired somatic mutations of IDH1 and IDH2 have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases.

Methods

Two-hundred and thirty newly diagnosed AML patients were analyzed for the presence of IDH1 and IDH2 heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the IDH mutational status. Coexisting mutations such as FLT3, PML- RARA, RAS, AML1, and NPM1 mutations were additionally explored.

Results

The prevalence of IDH1 and IDH2 mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among IDH1-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in IDH2-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual IDH1 and IDH2 mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had IDH mutations. Half of the IDH-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, IDH1- and IDH2-mutated cases predominantly had NPM1 mutations (60-74%) as compared to the wild type (P < 0.001). Very few IDH-mutated cases had FLT3 and/or RAS abnormalities and none of them had AML1 mutations. Older age and higher median platelet counts were significantly associated with IDH2 mutations although the clinical impact of either IDH1 or IDH2 mutations on patients' overall survival could not be observed.

Conclusion

Overall, 19% of newly diagnosed AML patients had alterations of IDH genes. No patients concurrently carried both IDH1 and IDH2 mutations suggesting that these mutations were mutually exclusive. NPM1 mutation appears as a major coexisting genetic mutation in IDH-mutated patients. Our present data failed to support the prognostic relevance of IDH mutations although alterations of these metabolic genes potentially have an important role in leukemia development.
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Literature
1.
Estey E, Dohner H: Acute myeloid leukaemia. Lancet. 2006, 368: 1894-1907. 10.1016/S0140-6736(06)69780-8.CrossRefPubMed
2.
Mrozek K, Heerema NA, Bloomfield CD: Cytogenetics in acute leukemia. Blood Rev. 2004, 18: 115-136. 10.1016/S0268-960X(03)00040-7.CrossRefPubMed
3.
Takahashi S: Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. J Hematol Oncol. 2011, 4: 13-10.1186/1756-8722-4-13.PubMedCentralCrossRefPubMed
4.
5.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD et al: Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009, 361: 1058-1066. 10.1056/NEJMoa0903840.PubMedCentralCrossRefPubMed
6.
Briere JJ, Favier J, Gimenez-Roqueplo AP, Rustin P: Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation. Am J Physiol Cell Physiol. 2006, 291: C1114-C1120. 10.1152/ajpcell.00216.2006.CrossRefPubMed
7.
Seyfried TN, Shelton LM: Cancer as a metabolic disease. Nutr Metab (Lond). 2010, 7: 7-10.1186/1743-7075-7-7.CrossRef
8.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC et al: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009, 462: 739-744. 10.1038/nature08617.PubMedCentralCrossRefPubMed
9.
Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y et al: Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009, 324: 261-265. 10.1126/science.1170944.PubMedCentralCrossRefPubMed
10.
Corpas FJ, Barroso JB, Sandalio LM, Palma JM, Lupianez JA, del Rio LA: Peroxisomal NADP-Dependent Isocitrate Dehydrogenase. Characterization and Activity Regulation during Natural Senescence. Plant Physiol. 1999, 121: 921-928. 10.1104/pp.121.3.921.PubMedCentralCrossRefPubMed
11.
Dang L, Jin S, Su SM: IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med. 2010, 16: 387-397. 10.1016/j.molmed.2010.07.002.CrossRefPubMed
12.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 2008, 321: 1807-1812. 10.1126/science.1164382.PubMedCentralCrossRefPubMed
13.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009, 360: 765-773. 10.1056/NEJMoa0808710.PubMedCentralCrossRefPubMed
14.
Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, Frattini M, Molinari F, Knowles M, Cerrato A et al: IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 2009, 30: 7-11. 10.1002/humu.20937.CrossRefPubMed
15.
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D, Holland KB, Whitman SP, Becker H, Schwind S 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. 10.1200/JCO.2009.27.3730.PubMedCentralCrossRefPubMed
16.
Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, Tefferi A: IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia. 2010, 24: 1146-1151. 10.1038/leu.2010.77.CrossRefPubMed
17.
Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, Hunault-Berger M, Slama B, Vey N, Lacombe C 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. 10.1038/leu.2010.52.CrossRefPubMed
18.
Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay W, Ko BS, Wu SJ, Huang SY, Hsu SC et al: Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation. Blood. 2010, 115: 2749-2754. 10.1182/blood-2009-11-253070.CrossRefPubMed
19.
Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM 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. 10.1084/jem.20092506.PubMedCentralCrossRefPubMed
20.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE 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. 10.1016/j.ccr.2010.01.020.PubMedCentralCrossRefPubMed
21.
Wagner K, Damm F, Gohring G, Gorlich K, Heuser M, Schafer I, Ottmann O, Lubbert M, Heit W, Kanz L 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. 10.1200/JCO.2009.27.6899.CrossRefPubMed
22.
Ho PA, Alonzo TA, Kopecky KJ, Miller KL, Kuhn J, Zeng R, Gerbing RB, Raimondi SC, Hirsch BA, Oehler V et al: Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia. 2010, 24: 909-913. 10.1038/leu.2010.56.PubMedCentralCrossRefPubMed
23.
Thol F, Damm F, Wagner K, Gohring G, Schlegelberger B, Hoelzer D, Lubbert M, Heit W, Kanz L, Schlimok G et al: Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood. 2010, 116: 614-616. 10.1182/blood-2010-03-272146.CrossRefPubMed
24.
Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A, van Putten WJ, Rijneveld AW, Lowenberg B, Valk PJ: 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. 10.1182/blood-2009-11-250878.CrossRefPubMed
25.
Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L, Spath D, Kayser S, Zucknick M, Gotze K 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. 10.1200/JCO.2010.28.3762.CrossRefPubMed
26.
Green CL, Evans CM, Zhao L, Hills RK, Burnett AK, Linch DC, Gale RE: The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011, 118: 409-412. 10.1182/blood-2010-12-322479.CrossRefPubMed
27.
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. 10.1182/blood-2010-02-267955.CrossRefPubMed
28.
Zou Y, Zeng Y, Zhang DF, Zou SH, Cheng YF, Yao YG: IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders. Biochem Biophys Res Commun. 2010, 402: 378-383. 10.1016/j.bbrc.2010.10.038.CrossRefPubMed
29.
Andersson AK, Miller DW, Lynch JA, Lemoff AS, Cai Z, Pounds SB, Radtke I, Yan B, Schuetz JD, Rubnitz JE et al: IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia. 2011, 25: 1570-1577. 10.1038/leu.2011.133.CrossRefPubMed
30.
Patel KP, Ravandi F, Ma D, Paladugu A, Barkoh BA, Medeiros LJ, Luthra R: Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011, 135: 35-45. 10.1309/AJCPD7NR2RMNQDVF.CrossRefPubMed
31.
Lin J, Qian J, Yao DM, Li Y, Yang J, Chen Q, Chai HY, Xiao GF, Xu WR: Rapid and reliable detection of IDH1 R132 mutations in acute myeloid leukemia using high-resolution melting curve analysis. Clin Biochem. 2011, 44: 779-783. 10.1016/j.clinbiochem.2011.04.014.CrossRefPubMed
32.
Zhang Y, Wei H, Wang M, Huai L, Mi Y, Zhang Y, Lin DT, Liu B, Li W, Zhou C et al: Some novel features of IDH1-mutated acute myeloid leukemia revealed in Chinese patients. Leuk Res. 2011, 35: 1301-1306. 10.1016/j.leukres.2011.01.019.CrossRefPubMed
33.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF 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. 10.1016/j.ccr.2010.11.015.PubMedCentralCrossRefPubMed
34.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Xiao MT, Liu LX et al: Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate- dependent dioxygenases. Cancer Cell. 2011, 19: 17-30. 10.1016/j.ccr.2010.12.014.PubMedCentralCrossRefPubMed
35.
Auewarakul CU, Sritana N, Limwongse C, Thongnoppakhun W, Yenchitsomanus PT: Mutations of the FLT3 gene in adult acute myeloid leukemia: determination of incidence and identification of a novel mutation in a Thai population. Cancer Genet Cytogenet. 2005, 162: 127-134. 10.1016/j.cancergencyto.2005.03.011.CrossRefPubMed
36.
Auewarakul CU, Lauhakirti D, Tocharoentanaphol C: Frequency of RAS gene mutation and its cooperative genetic events in Southeast Asian adult acute myeloid leukemia. Eur J Haematol. 2006, 77: 51-56. 10.1111/j.1600-0609.2006.00663.x.CrossRefPubMed
37.
Auewarakul CU, Leecharendkeat A, Tocharoentanaphol C, Promsuwicha O, Sritana N, Thongnoppakhun W: AML1 mutation and its coexistence with different transcription factor gene families in de novo acute myeloid leukemia (AML): redundancy or synergism. Haematologica. 2007, 92: 861-862. 10.3324/haematol.10914.CrossRefPubMed
38.
Boonthimat C, Thongnoppakhun W, Auewarakul CU: Nucleophosmin mutation in Southeast Asian acute myeloid leukemia: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations. Haematologica. 2008, 93: 1565-1569. 10.3324/haematol.12937.CrossRefPubMed
39.
Promsuwicha O, Thongnoppakhun W, Wongkhantee S, Tocharoentanaphol C, Auewarakul CU: Molecular characterization of PML-RARα fusion gene with acute promyelocytic leukemia (APL) by nested RT-PCR. Thai J Hematol Transf Med. 2005, 15: 247-257.
40.
Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958, 53: 457-481. 10.2307/2281868.CrossRef
41.
Boissel N, Nibourel O, Renneville A, Gardin C, Reman O, Contentin N, Bordessoule D, Pautas C, de Revel T, Quesnel B 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. 10.1200/JCO.2010.28.2285.CrossRefPubMed
42.
Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A: Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005, 105: 973-977.CrossRefPubMed
43.
Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M, Gohring G, Schumann C, Bug G, Ottmann O et al: IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica. 2010, 95: 1668-1674. 10.3324/haematol.2010.025494.PubMedCentralCrossRefPubMed
44.
Green A, Beer P: Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 2010, 362: 369-370. 10.1056/NEJMc0910063.CrossRefPubMed
45.
Pardanani A, Patnaik MM, Lasho TL, Mai M, Knudson RA, Finke C, Ketterling RP, McClure RF, Tefferi A: Recurrent IDH mutations in high-risk myelodysplastic syndrome or acute myeloid leukemia with isolated del(5q). Leukemia. 2010, 24: 1370-1372. 10.1038/leu.2010.98.CrossRefPubMed
46.
Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D, Pieri L, Finke CM, Kilpivaara O, Wadleigh M 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. 10.1038/leu.2010.113.PubMedCentralCrossRefPubMed
Metadata
Title
Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients
Authors
Sadudee Chotirat
Wanna Thongnoppakhun
Orathai Promsuwicha
Chetsada Boonthimat
Chirayu U Auewarakul
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2012
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/1756-8722-5-5

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