Top

Published in:

01-06-2016 | Progress in Hematology

Roles of IDH1/2 and TET2 mutations in myeloid disorders

Authors: Satoshi Inoue, François Lemonnier, Tak W. Mak

Published in: International Journal of Hematology | Issue 6/2016

Abstract

Mutations of the epigenetic enzymes isocitrate dehydrogenase (IDH) 1 and 2, and the methylcytosine dioxygenase ‘ten–eleven translocation 2’ (TET2), are common in human myeloid malignancies and drivers of these disorders but the underlying mechanisms remain obscure. This review examines mutant IDH1/2 and TET2 enzymes in the context of responses to DNA damage and their potential involvement in age-related genomic instability. The clinical relevance of these findings and their potential application in novel therapeutic strategies is also discussed.

Shih AH, Abdel-Wahab O, Patel JP, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer. 2012;12(9):599–612.CrossRefPubMed

Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8.CrossRefPubMedPubMedCentral

Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M, Lamant L, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120(7):1466–9.CrossRefPubMed

Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98.CrossRefPubMedPubMedCentral

Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44(11):1179–81.CrossRefPubMedPubMedCentral

Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRef

Cimmino L, Dawlaty MM, Ndiaye-Lobry D, Yap YS, Bakogianni S, Yu Y, et al. TET1 is a tumor suppressor of hematopoietic malignancy. Nat Immunol. 2015;16(6):653–62.CrossRefPubMedPubMedCentral

An J, Gonzalez-Avalos E, Chawla A, Jeong M, Lopez-Moyado IF, Li W, et al. Acute loss of TET function results in aggressive myeloid cancer in mice. Nat Commun. 2015;6:10071.CrossRefPubMedPubMedCentral

Zhao Z, Chen L, Dawlaty MM, Pan F, Weeks O, Zhou Y, et al. Combined loss of Tet1 and Tet2 promotes B cell, but not myeloid malignancies, in mice. Cell Rep. 2015;13(8):1692–704.CrossRefPubMedPubMedCentral

10.

Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300–3.CrossRefPubMedPubMedCentral

11.

Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145(3):423–34.CrossRefPubMedPubMedCentral

12.

Chen Q, Chen Y, Bian C, Fujiki R, Yu X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature. 2013;493(7433):561–4.CrossRefPubMed

13.

Dawlaty MM, Breiling A, Le T, Barrasa MI, Raddatz G, Gao Q, et al. Loss of Tet enzymes compromises proper differentiation of embryonic stem cells. Dev Cell. 2014;29(1):102–11.CrossRefPubMedPubMedCentral

14.

Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.CrossRefPubMedPubMedCentral

15.

Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20(1):25–38.CrossRefPubMed

16.

Shih AH, Jiang Y, Meydan C, Shank K, Pandey S, Barreyro L, et al. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell. 2015;27(4):502–15.CrossRefPubMedPubMedCentral

17.

Kroeze LI, Aslanyan MG, van Rooij A, Koorenhof-Scheele TN, Massop M, Carell T, et al. Characterization of acute myeloid leukemia based on levels of global hydroxymethylation. Blood. 2014;124(7):1110–8.CrossRefPubMed

18.

Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3(7):730–41.CrossRefPubMed

19.

Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119(8):1901–3.CrossRefPubMedPubMedCentral

20.

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.CrossRefPubMedPubMedCentral

21.

Achouri Y, Noel G, Vertommen D, Rider MH, Veiga-Da-Cunha M, Van Schaftingen E. Identification of a dehydrogenase acting on d-2-hydroxyglutarate. Biochem J. 2004;381(Pt 1):35–42.CrossRefPubMedPubMedCentral

22.

Rzem R, Veiga-da-Cunha M, Noel G, Goffette S, Nassogne MC, Tabarki B, et al. A gene encoding a putative FAD-dependent l-2-hydroxyglutarate dehydrogenase is mutated in l-2-hydroxyglutaric aciduria. Proc Natl Acad Sci USA. 2004;101(48):16849–54.CrossRefPubMedPubMedCentral

23.

Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS, et al. IDH2 mutations in patients with d-2-hydroxyglutaric aciduria. Science. 2010;330(6002):336.CrossRefPubMed

24.

Intlekofer AM, Dematteo RG, Venneti S, Finley LW, Lu C, Judkins AR, et al. Hypoxia induces production of l-2-hydroxyglutarate. Cell Metab. 2015;22(2):304–11.CrossRefPubMed

25.

Oldham WM, Clish CB, Yang Y, Loscalzo J. Hypoxia-mediated increases in l-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 2015;22(2):291–303.CrossRefPubMed

26.

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(5):463–9.CrossRefPubMedPubMedCentral

27.

Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479–83.CrossRefPubMedPubMedCentral

28.

Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, et al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 2012;26(18):2038–49.CrossRefPubMedPubMedCentral

29.

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(1):17–30.CrossRefPubMedPubMedCentral

30.

Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483(7390):484–8.CrossRefPubMedPubMedCentral

31.

Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, et al. IDH1 (R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012;488(7413):656–9.CrossRefPubMedPubMedCentral

32.

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(2):178–84.CrossRefPubMedPubMedCentral

33.

Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2):264–78.CrossRefPubMedPubMedCentral

34.

Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301.CrossRefPubMed

35.

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(6):553–67.CrossRefPubMedPubMedCentral

36.

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(7):2548–53.CrossRefPubMedPubMedCentral

37.

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(7488):328–33.CrossRefPubMed

38.

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(1):101–5.CrossRefPubMed

39.

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(10):1668–74.CrossRefPubMedPubMedCentral

40.

Molenaar RJ, Thota S, Nagata Y, Patel B, Clemente M, Przychodzen B, et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia. 2015;29(11):2134–42.CrossRefPubMed

41.

Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46(2):171–5.CrossRefPubMed

42.

Wang C, McKeithan TW, Gong Q, Zhang W, Bouska A, Rosenwald A, et al. IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood. 2015;126(15):1741–52.CrossRefPubMed

43.

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(12):1079–89.CrossRefPubMedPubMedCentral

44.

Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 2008;8(3):193–204.CrossRefPubMed

45.

Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell. 2014;15(1):37–50.CrossRefPubMedPubMedCentral

46.

Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell. 2010;7(2):174–85.CrossRefPubMedPubMedCentral

47.

Krivtsov AV, Figueroa ME, Sinha AU, Stubbs MC, Feng Z, Valk PJ, et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia. 2013;27(4):852–60.CrossRefPubMed

48.

Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med. 2012;4(149):149ra18.CrossRef

49.

Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431(7011):997–1002.CrossRefPubMed

50.

Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447(7145):686–90.CrossRefPubMed

51.

Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447(7145):725–9.CrossRefPubMed

52.

Brandwein JM, Kassis J, Leber B, Hogge D, Howson-Jan K, Minden MD, et al. Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6)-methylguanine DNA methyltransferase expression. Br J Haematol. 2014;167(5):664–70.CrossRefPubMed

53.

Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, et al. Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Res. 2015;75(22):4790–802.CrossRefPubMed

54.

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(6132):626–30.CrossRefPubMedPubMedCentral

55.

Wang P, Wu J, Ma S, Zhang L, Yao J, Hoadley KA, et al. Oncometabolite d-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep. 2015;13(11):2353–61.CrossRefPubMedPubMedCentral

56.

Esposito MT, Zhao L, Fung TK, Rane JK, Wilson A, Martin N, et al. Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med. 2015;21(12):1481–90.CrossRefPubMed

Title: Roles of IDH1/2 and TET2 mutations in myeloid disorders
Authors: Satoshi Inoue
François Lemonnier
Tak W. Mak
Publication date: 01-06-2016
Publisher: Springer Japan
Published in: International Journal of Hematology / Issue 6/2016
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-016-1973-7

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2016

Efficacy of upfront high-dose chemotherapy plus rituximab followed by autologous peripheral blood stem cell transplantation for untreated high-intermediate-, and high-risk diffuse large B-cell lymphoma: a multicenter prospective phase II study (JSCT-NHL04)

Guest editorial: Cooperative networks for stem cell homeostasis in normal and malignant hematopoiesis: from metabolism to epigenetics

DNA methylation in normal and malignant hematopoiesis

Iron overload, G6PD deficiency, and lead levels on blood smears

The roles of Polycomb group proteins in hematopoietic stem cells and hematological malignancies

A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia

Keynote webinar | Spotlight on antibody–drug conjugates in cancer