Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms

Molenaar, Remco J.; Thota, Swapna; Nagata, Yasunobu; Patel, Bhumika J.; Clemente, Michael J.; Przychodzen, Bartlomiej; Hirsh, Cassandra; Viny, Aaron D.; Hosano, N.; Bleeker, Fonnet E.; Meggendorfer, Manja; Alpermann, Tamara; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Noorden, C. J. F. Van; Radivoyevitch, Tomas; Carraway, Hetty E.; Makishima, Hideki; Miyano, Satoru; Sekeres, Mikkael A.; Ogawa, Seishi; Haferlach, Torsten; Maciejewski, Jaroslaw P.

doi:10.1038/leu.2015.91

Cited by 80 publications

(79 citation statements)

References 34 publications

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“…The combined effects of all these changes lead to a block in myeloid differentiation and accumulation of DNA damage in HSC/myeloid progenitors that is oncogenic unlike TET2 mutations, IDH1/2 mutations are quite rare in clonal hematopoiesis of indeterminate potential. IDH1/2 mutation frequency is higher in de novo AML than in chronic myeloid neoplasms [40], whereas the greatest incidence (50 %) of TET2 mutations occurs in CMML, in agreement with the myelomonocytic proliferation in TET2 KO mice. Thus, IDH1/2 mutations appear to have higher oncogenic potential than TET2 mutations and are associated with more aggressive diseases [1,2].…”

Section: Tet2 and Idh1/2 Mutations In Hematological Disorderssupporting

confidence: 53%

Roles of IDH1/2 and TET2 mutations in myeloid disorders

2016

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Although mutated IDH1/2 are clearly established as oncogenes in myeloid cells, the mechanisms underlying their tumorigenic effects are not clear. Much evidence suggests that mutant IDH enzymes exert their effects via inhibition of TET2, but important clinical differences between IDH1-mutant and TET2-mutant hematopoietic disorders suggest that the oncogenic mechanisms of these mutated enzymes may differ. In particular, divergent effects of mutant IDH1/2 and TET2 on DNA damage repair mechanisms have been identified. In this review, we examine mutant IDH1/2 and TET2 in the context of responses to DNA damage and their potential involvement in genomic instability. We also discuss the clinical relevance of these findings and their potential application in novel therapeutic strategies. Mutation of TET family enzymesThe TET family of dioxygenases is highly conserved and contains three members: TET1, -2 and -3. Somatic mutations of TET2 occur in various myeloid disorders, including chronic myelomonocytic leukemia (CMML) (~50 %), myeloid proliferative neoplasm (MPN) (~13 %), MDS (~25 %) and AML (~23 %) [1,2]. TET2 is also mutated in B and T cell lymphoid malignancies, including angioimmunoblastic T cell lymphoma (AITL) [3]. More recently, TET2 mutations have been detected in elderly individuals with clonal hematopoiesis of indeterminate potential, i.e.: individuals with clonal hematopoiesis without identified hematological disease. This indicates that TET2 mutations alone cannot drive leukemogenesis and that additional events probably contribute [4,5]. Interestingly, TET1 and TET3 mutations are rare in human hematological diseases [6]. This predominance of TET2 alterations is not 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.

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Section: Tet2 and Idh1/2 Mutations In Hematological Disorderssupporting

confidence: 53%

Roles of IDH1/2 and TET2 mutations in myeloid disorders

2016

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“…MT confer a worse prognosis in AML patients (45). One difference between AML and glioma is that IR is typically not used to treat AML, whereas it is routinely used as a treatment modality for glioma.…”

Section: Idhmentioning

confidence: 99%

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

et al. 2015

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Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1 R132H , a structural alteration that leads to catalysis of a-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1 R132H that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1 R132H mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1 R132H inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1 R132H inhibitors in these patients may limit irradiation efficacy in this setting.

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“…6,[8][9][10] Although both mutations are characterized by neomorphic enzymatic activity, myeloid malignancies with R140 and R172 IDH2 mutations are distinct with respect to clinical outcome, comutational profile, and molecular classification. [11][12][13] In preclinical studies, enasidenib (AG-221/CC-90007), a small-molecule inhibitor of mIDH2, reduced serum 2-HG, DNA hypermethylation, and repressive histone marks and promoted hematopoietic differentiation in R140 and R172 mIDH2 models. [14][15][16][17] In a phase 1/2 clinical trial, enasidenib demonstrated clinical activity in patients with both R140 and R172 mIDH2 relapsed/refractory AML (rrAML) with an overall response rate (ORR) of 40.3%.…”

Section: Introductionmentioning

confidence: 99%

Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response

Amatangelo¹,

Quek

Shih

et al. 2017

Blood

316

307

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• Enasidenib inhibits mIDH2, leading to leukemic cell differentiation with emergence of functional mIDH2 neutrophils in rrAML patients.• RAS pathway mutations and increased mutational burden overall are associated with a decreased response rate to mIDH2 inhibition.Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies. (Blood. 2017;130(6):732-741)

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Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms

Cited by 80 publications

References 34 publications

Roles of IDH1/2 and TET2 mutations in myeloid disorders

Roles of IDH1/2 and TET2 mutations in myeloid disorders

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response

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