Author/Authors :
Figueroa، نويسنده , , Maria E. and Abdel-Wahab، نويسنده , , Omar and Lu، نويسنده , , Chao and Ward، نويسنده , , Patrick S. and Patel، نويسنده , , Jay and Shih، نويسنده , , Alan and Li، نويسنده , , Yushan and Bhagwat، نويسنده , , Neha and Vasanthakumar، نويسنده , , Aparna and Fernandez، نويسنده , , Hugo F. and Tallman، نويسنده , , Martin S. and Sun، نويسنده , , Zhuoxin and Wolniak، نويسنده , , Kristy and Peeters، نويسنده , , Justine K. and Liu، نويسنده , , Wei and Choe، نويسنده , , Sung E. and Fantin، نويسنده , , Valeria R. and Paietta، نويسنده , , Elisabeth and Lِwenberg، نويسنده , , Bob and Licht، نويسنده , , Jonathan D. and Godley، نويسنده , , Lucy A. and Delwel، نويسنده , , Ruud and Valk، نويسنده , , Peter J.M. and Thompson، نويسنده , , Craig B. and Levine، نويسنده , , Ross L. and Melnick، نويسنده , , Ari، نويسنده ,
Abstract :
Summary
-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 α-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.
