Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

作者：Figueroa Maria E; Abdel Wahab Omar; Lu Chao; Ward Patrick S; Patel Jay; Shih Alan; Li Yushan; Bhagwat Neha; Vasanthakumar Aparna; Fernandez Hugo F; Tallman Martin S; Sun Zhuoxin; Wolniak Kristy; Peeters Justine K; Liu Wei; Choe Sung E; Fantin Valeria R; Paietta Elisabeth; Lowenberg Bob; Licht Jonathan D; Godley Lucy A; Delwel Ruud; Valk Peter J M; Thompson Craig B^*; Levine Ross L; Melnick An

来源：Cancer Cell, 2010, 18(6): 553-567.

DOI：10.1016/j.ccr.2010.11.015

Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (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 alpha-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were 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.

• 出版日期2010-12-14
• 单位西北大学