Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

By Maria E. Figueroa, Omar Abdel Wahab, Chao Lu, Patrick S. Ward, Jay L. Patel, A. Shih, Yushan Li, Neha Bhagwat, A. Vasanthakumar, H. Fernandez and 16 more. Cancer Cell, 2010

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Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/706a8592f603e38528389739fa192c92e542776d

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Otto Warburg's contributions to current concepts of cancer metabolism (2011, background): “Thus, tumorigenesis is enhanced through the modification of the epigenom”
Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. (2017, neutral): “Platelets, 310(9)/L 39 (1-372) 44 (1-507) 45 (1-644)”
Lessons from the cancer genome. (2013, neutral): “This large-scale study showed that IDH1/IDH2mutations were mutually exclusive with inactivating TET2 mutations (Figueroa et al., 2010), suggesting that the two types of mutations had similar effects and were thus functionally redundant.”
A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “For example, mutations in the TET2 , isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 genes occur in gliomas and leukaemi”
WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation (2015, positive): “, 2011), which occurs in about 20% of AMLs in a mutually exclusive manner with TET2 mutations (Figueroa et al., 2010).”
Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. (2013, positive): “Furthermore, mutations in IDH1 and -2, which generate 2-oxo-glutarate, are phenocopied by mutations in the TET enzymes and result in cancer (Figueroa et al., 2010).”
Metabolic requirements for the maintenance of self-renewing stem cells (2014, background): “The PML tumour-suppressor gene, which was originally cloned at the break point of the t(15;17) chromosomal translocation of acute promyelocytic leukaemia, has a key role in stem cell biology126.”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Collective evidence stemming from several reports have highlighted that the pathophysiological role of 2HG is, at least in part, the competitive inhibition of various αKG-dependent dioxygenases, including TET2 DNA hydroxylases and JmjC histone demethylases (91, 92).”
Epigenetic Determinants of Cancer. (2016, background): “Mutations in selected epigenetic modifiers in human cancers Process Gene Function Tumor type Alteration DNA methylation DNMT1 DNA methyltransferase Colorectal, Non–small cell lung, pancreatic, gastric, breast cancer Mutation (Kanai et al. 2003) Overexpression (Wu et al. 2007) DNMT3A DNA methyltransf”