Isocitrate dehydrogenase mutations in myeloid malignancies

Leukemia

Volumn 31, Issue 2, 2017, Pages 272-281

  Medeiros, B C ^a   Fathi, A T ^b   DiNardo, C D ^c   Pollyea, D A ^d   Chan, S M ^e   Swords, R ^f  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^d UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

^e PRINCESS MARGARET HOSPITAL   (Canada)

^f UNIVERSITY OF MIAMI   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AG 120; AG 881; ANTINEOPLASTIC AGENT; CB 839; DNA METHYLTRANSFERASE INHIBITOR; ENASIDENIB; FT 2102; IDH 305; ISOCITRATE DEHYDROGENASE; ISOCITRATE DEHYDROGENASE INHIBITOR; RETINOIC ACID; SMALL MOLECULE TRANSPORT AGENT; UNCLASSIFIED DRUG; VENETOCLAX; ISOENZYME; TUMOR MARKER;

ACUTE MYELOID LEUKEMIA; CANCER CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER EPIDEMIOLOGY; CANCER PROGNOSIS; DRUG TARGETING; GENE MUTATION; HUMAN; INDUCTION CHEMOTHERAPY; META ANALYSIS (TOPIC); MUTATIONAL ANALYSIS; MYELODYSPLASTIC SYNDROME; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; ANIMAL; DNA MUTATIONAL ANALYSIS; ENZYMOLOGY; GENE FREQUENCY; GENETICS; LEUKEMIA, MYELOID, ACUTE; METABOLISM; MORTALITY; MUTATION; MYELODYSPLASTIC SYNDROMES; PROGNOSIS;

ANIMALS; BIOMARKERS, TUMOR; DNA MUTATIONAL ANALYSIS; GENE FREQUENCY; HUMANS; ISOCITRATE DEHYDROGENASE; ISOENZYMES; LEUKEMIA, MYELOID, ACUTE; MUTATION; MYELODYSPLASTIC SYNDROMES; PROGNOSIS;

EID: 84994772429     PISSN: 08876924     EISSN: 14765551     Source Type: Journal    
DOI: 10.1038/leu.2016.275     Document Type: Review

References (106)

1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med 2015; 373: 1136-1152.
2. Albitar M, Manshouri T, Shen Y, Liu D, Beran M, Kantarjian HM et al. Myelodysplastic syndrome is not merely 'preleukemia'. Blood 2002; 100: 791-798.
3. 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.
4. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85-95.
5. Conway O'Brien E, Prideaux S, Chevassut T. The epigenetic landscape of acute myeloid leukemia. Adv Hematol 2014; 2014: 103175.
6. Clark O, Yen K, Mellinghoff IK. Molecular pathways: isocitrate dehydrogenase mutations in cancer. Clin Cancer Res 2016; 22: 1-7.
7. Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE. The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim Biophys Acta 2014; 1846: 326-341.
8. Stein EM. Molecular pathways: IDH2 mutations-co-opting cellular metabolism for malignant transformation. Clin Cancer Res 2016; 22: 16-19.
9. Willander K, Falk IJ, Chaireti R, Paul E, Hermansson M, Green H et al. Mutations in the isocitrate dehydrogenase 2 gene and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia. Biomark Res 2014; 2: 18.
10. 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.
11. 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.
12. Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: not your typical oncogenes. Cancer Cell 2010; 17: 215-216.
13. Losman JA, Kaelin WG Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 2013; 27: 836-852.
14. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancerassociated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462: 739-744.
15. Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Goparaju R, Schwarzer A et al. Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia 2016; 30: 1708-1715.
16. Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339: 1621-1625.
17. Ward PS, Lu C, Cross JR, Abdel-Wahab O, Levine RL, Schwartz GK et al. The potential for isocitrate dehydrogenase mutations to produce 2-hydroxyglutarate depends on allele specificity and subcellular compartmentalization. J Biol Chem 2013; 288: 3804-3815.
18. Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 2015; 21: 178-184.
19. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17-30.
20. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 2011; 12: 463-469.
21. Chan SM, Majeti R. Role of DNMT3A, TET2, and IDH1/2 mutations in pre-leukemic stem cells in acute myeloid leukemia. Int J Hematol 2013; 98: 648-657.
22. Accari SL, Fisher PR. Emerging roles of JmjC domain-containing proteins. Int Rev Cell Mol Biol 2015; 319: 165-220.
23. Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res 2012; 18: 5562-5571.
24. Prensner JR, Chinnaiyan AM. Metabolism unhinged: IDH mutations in cancer. Nat Med 2011; 17: 291-293.
25. 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.
26. Jin G, Reitman ZJ, Duncan CG, Spasojevic I, Gooden DM, Rasheed BA et al. Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. Cancer Res 2013; 73: 496-501.
27. Fathi AT, Wander SA, Faramand R, Emadi A. Biochemical, epigenetic, and metabolic approaches to target IDH mutations in acute myeloid leukemia. Semin Hematol 2015; 52: 165-171.
28. Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 2013; 121: 3563-3572.
29. 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.
30. Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA 2014; 111: 2548-2553.
31. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328-333.
32. Im AP, Sehgal AR, Carroll MP, Smith BD, Tefferi A, Johnson DE et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia 2014; 28: 1774-1783.
33. Stein EM. IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol 2015; 28: 112-115.
34. Platt MY, Fathi AT, Borger DR, Brunner AM, Hasserjian RP, Balaj L et al. Detection of dual IDH1 and IDH2 mutations by targeted next-generation sequencing in acute myeloid leukemia and myelodysplastic syndromes. J Mol Diagn 2015; 17: 661-668.
35. DiNardo CD, Ravandi F, Agresta S, Konopleva M, Takahashi K, Kadia T et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol 2015; 90: 732-736.
36. Molenaar RJ, Thota S, Nagata Y, Patel B, Clemente M, Hirsh C et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 2015; 29: 2134-2142.
37. Aref S, Kamel Areidael S, Abdel Aaal MF, Adam OM, El-Ghonemy MS, El-Baiomy MA et al. Prevalence and clinical effect of IDH1 and IDH2 mutations among cytogenetically normal acute myeloid leukemia patients. Clin Lymphoma Myeloma Leuk 2015; 15: 550-555.
38. 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.
39. DiNardo CD, Jabbour E, Ravandi F, Takahashi K, Daver N, Routbort M et al. IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. Leukemia 2016; 30: 980-984.
40. 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.
41. Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay W et al. Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation. Blood 2010; 115: 2749-2754.
42. Patel KP, Ravandi F, Ma D, Paladugu A, Barkoh BA, Medeiros LJ et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol 2011; 135: 35-45.
43. 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.
44. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079-1089.
45. Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J et al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep 2014; 9: 1841-1855.
46. Lin CC, Hou HA, Chou WC, Kuo YY, Liu CY, Chen CY et al. IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution. Am J Hematol 2014; 89: 137-144.
47. Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood 2012; 120: 4168-4171.
48. Feng JH, Guo XP, Chen YY, Wang ZJ, Cheng YP, Tang YM. Prognostic significance of IDH1 mutations in acute myeloid leukemia: a meta-analysis. Am J Blood Res 2012; 2: 254-264.
49. Yamaguchi S, Iwanaga E, Tokunaga K, Nanri T, Shimomura T, Suzushima H et al. IDH1 and IDH2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1 mutation. Eur J Haematol 2014; 92: 471-477.
50. Chotirat S, Thongnoppakhun W, Promsuwicha O, Boonthimat C, Auewarakul CU. Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients. J Hematol Oncol 2012; 5: 5.
51. 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.
52. 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.
53. Abdel-Karim I, Plunkett Jr WK, O'Brien S, Giles F, Thomas D, Faderl S et al. A phase I study of pemetrexed in patients with relapsed or refractory acute leukemia. Invest New Drugs 2011; 29: 323-331.
54. Boissel N, Nibourel O, Renneville A, Huchette P, Dombret H, Preudhomme C. Differential prognosis impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 2011; 117: 3696-3697.
55. 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.
56. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016; 374: 2209-2221.
57. Ravandi F, Patel K, Luthra R, Faderl S, Konopleva M, Kadia T et al. Prognostic significance of alterations in IDH enzyme isoforms in patients with AML treated with high-dose cytarabine and idarubicin. Cancer 2012; 118: 2665-2673.
58. Sloan CE, Luskin MR, Boccuti AM, Sehgal AR, Zhao J, Daber RD et al. A modified integrated genetic model for risk prediction in younger patients with acute myeloid leukemia. PLoS One 2016; 11: e0153016.
59. 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.
60. Jin J, Hu C, Yu M, Chen F, Ye L, Yin X et al. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLoS One 2014; 9: e100206.
61. Bejar R, Papaemmanuil E, Haferlach T, Garcia-Manero G, Maciejewski J, Sekeres M et al. Somatic mutations in MDS patients are associated with clinical features and predict prognosis independent of the IPSS-R: Analysis of combined datasets from the International Working Group for Prognosis in MDS-Molecular Committee. Blood 2015; 126: 907.
62. Patnaik MM, Hanson CA, Hodnefield JM, Lasho TL, Finke CM, Knudson RA et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients. Leukemia 2012; 26: 101-105.
63. Wang JH, Chen WL, Li JM, Wu SF, Chen TL, Zhu YM et al. Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China. Proc Natl Acad Sci USA 2013; 110: 17017-17022.
64. DiNardo CD, Propert KJ, Loren AW, Paietta E, Sun Z, Levine RL et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood 2013; 121: 4917-4924.
65. Janin M, Mylonas E, Saada V, Micol JB, Renneville A, Quivoron C et al. Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol 2014; 32: 297-305.
66. Mahdieh N, Rabbani B. An overview of mutation detection methods in genetic disorders. Iran J Pediatr 2013; 23: 375-388.
67. Patel KP, Barkoh BA, Chen Z, Ma D, Reddy N, Medeiros LJ et al. Diagnostic testing for IDH1 and IDH2 variants in acute myeloid leukemia an algorithmic approach using high-resolution melting curve analysis. J Mol Diagn 2011; 13: 678-686.
68. Horbinski C, Kelly L, Nikiforov YE, Durso MB, Nikiforova MN. Detection of IDH1 and IDH2 mutations by fluorescence melting curve analysis as a diagnostic tool for brain biopsies. J Mol Diagn 2010; 12: 487-492.
69. Gorniak P, Ejduk A, Borg K, Makuch-Lasica H, Nowak G, Lech-Maranda E et al. Comparison of high-resolution melting analysis with direct sequencing for the detection of recurrent mutations in DNA methyltransferase 3A and isocitrate dehydrogenase 1 and 2 genes in acute myeloid leukemia patients. Eur J Haematol 2016; 96: 181-187.
70. Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Gorlich D et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood 2016; 128: 686-698.
71. McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J et al. Leukemiaassociated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep 2015; 10: 1239-1245.
72. Debarri H, Lebon D, Roumier C, Cheok M, Marceau-Renaut A, Nibourel O et al. IDH1/2 but not DNMT3A mutations are suitable targets for minimal residual disease monitoring in acute myeloid leukemia patients: a study by the Acute Leukemia French Association. Oncotarget 2015; 6: 42345-42353.
73. Stein EM, DiNardo C, Altman JK, Collins R, DeAngelo DJ, Kantarjian HM et al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: Results of a phase 1/2 trial. Blood 2015; 126: 323.
74. DiNardo C, de Botton S, Pollyea DA, Stein EM, Fathi AT, Roboz GJ et al. Molecular profiling and relationship with clinical response in patients with IDH1 mutationpositive hematologic malignancies receiving AG-120, a first-in-class potent inhibitor of mutant IDH1, in addition to data from the completed dose escalation portion of the phase 1 study. Blood 2015; 126: Abstract 1306.
75. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126: 9-16.
76. Fathi AT, Sadrzadeh H, Borger DR, Ballen KK, Amrein PC, Attar EC et al. Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response. Blood 2012; 120: 4649-4652.
77. Balss J, Pusch S, Beck AC, Herold-Mende C, Kramer A, Thiede C et al. Enzymatic assay for quantitative analysis of (D)-2-hydroxyglutarate. Acta Neuropathol 2012; 124: 883-891.
78. Brunner AM, Neuberg D, Wander SA, Sadrzadeh H, Ballen KK, Amrein PC et al. Use of 2HG levels in the serum, urine, or bone marrow to predict IDH mutations in adults with acute myeloid leukemia. Blood 2015; 126: 2597-2597.
79. Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Yun H, Gorlich K et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 2013; 122: 2877-2887.
80. Wang F, Travins J, Lin Z, Si Y, Chen Y, Powe J et al. A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model. J Inherit Metab Dis 2016; 39: 807-820.
81. Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg A et al. Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells. PLoS One 2015; 10: e0133813.
82. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126: 291-299.
83. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30: 2670-2677.
84. Fenaux P, Ades L. Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. Leuk Res 2009; 33(Suppl 2): S7-S11.
85. Emadi A, Faramand R, Carter-Cooper B, Tolu S, Ford LA, Lapidus RG et al. Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia. Am J Hematol 2015; 90: E77-E79.
86. DiNardo CD, Patel KP, Garcia-Manero G, Luthra R, Pierce S, Borthakur G et al. Lack of association of IDH1, IDH2 and DNMT3A mutations with outcome in older patients with acute myeloid leukemia treated with hypomethylating agents. Leuk Lymphoma 2014; 55: 1925-1929.
87. Heuser M, Araujo Cruz MM, Goparaju R, Chaturvedi A. Enigmas of IDH mutations in hematology/oncology. Exp Hematol 2015; 43: 685-697.
88. Yaqub F. Inhibition of mutant IDH1 in acute myeloid leukaemia. Lancet Oncol 2015; 16: e9.
89. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013; 340: 622-626.
90. Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C et al. IDH2 mutationinduced histone and DNA hypermethylation is progressively reversed by smallmolecule inhibition. Blood 2015; 125: 296-303.
91. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013; 340: 626-630.
92. de Botton S, Pollyea DA, Stein EM, Dinardo C, Fathi AT, Roboz GJ et al. Clinical safety and activity of AG-120, a first-in-class potent inhibitor of the IDH1 mutant protein, in a phase 1 study of patients with advanced, IDH1-mutant hematological malignancies. Haematologica 2015; 100: Abstract P563.
93. Fan B, Le K, Manyak E, Liu H, Prahl M, Bowden C et al. Longitudinal pharmacokinetic/pharmacodynamic profile of AG-120, a potent inhibitor of the IDH1 mutant protein, in a phase 1 study of IDH1-mutant advanced hematologic malignancies. Blood 2015; 126: Abstract 1310.
94. Fan B, Chen Y, Wang F, Yen K, Utley L, Almon C et al. Pharmacokinetic/pharmacodynamic (PK/PD) evaluation of AG-221, a potent mutant IDH2 inhibitor, from a phase 1 trial of patients with IDH2 mutation-positive hematologic malignancies. Haematologica 2015; 100: Abstract 379.
95. Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood 2016; 127: 71-78.
96. Agios Pharmaceuticals. Agios Pharmaceuticals selects third novel IDH mutant inhibitor, AG-881, for clinical development. (News release). 2015 (cited 28 March 2016); available from http://investor.agios.com/phoenix.zhtml?c=251862&p=irol-newsArticle&ID=2041339.
97. Konopleva M, Pollyea DA, Potluri J, Chyla BJ, Busman T, McKeegan E et al. A phase 2 study of ABT-199 (GDC-0199) in patients with acute myelogenous leukemia (AML). Blood 2014; 124: Abstract 118.
98. Pollyea DA, DiNardo CD, thirman MJ, Letai A, Wei AH, Jonas BA et al. Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥65 years ineligible for standard induction therapy. J Clin Oncol 2016; 34(Suppl): Abstract 7009.
99. Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp Hematol 2014; 42: 247-251.
100. Wang ES, Frankfurt O, Orford KW, Bennett M, Flinn IW, Maris M et al. Phase 1 study of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase in patients with relapsed/refractory leukemia. Blood 2015; 126: Abstract 2566.
101. Schenk T, Chen WC, Gollner S, Howell L, Jin L, Hebestreit K et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 2012; 18: 605-611.
102. Boutzen H, Saland E, Cathebras M, Larrue C, Farge T, Serhan N et al. The combination of ATRA and dasatinib for differentiation therapy in acute myeloid leukemias with IDH mutations. Blood 2015; 126: Abstract 2542.
103. Estey E, Levine RL, Lowenberg B. Current challenges in clinical development of 'targeted therapies': the case of acute myeloid leukemia. Blood 2015; 125: 2461-2466.
104. Graubert T, Walter MJ. Genetics of myelodysplastic syndromes: new insights. Hematology: The Education Program of the American Society of Hematology 2011; 2011: 543-549.
105. Chotirat S, Thongnoppakhun W, Wanachiwanawin W, Auewarakul CU. Acquired somatic mutations of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) in preleukemic disorders. Blood Cells Mol Dis 2015; 54: 286-291.
106. 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.