TitleLeukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.
Publication TypeJournal Article
Year of Publication2010
AuthorsFigueroa, 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, Löwenberg Bob, Licht Jonathan D., Godley Lucy A., Delwel Ruud, Valk Peter J. M., Thompson Craig B., Levine Ross L., and Melnick Ari
JournalCancer Cell
Date Published2010 Dec 14
Keywords5-Methylcytosine, Cell Differentiation, Dioxygenases, DNA Methylation, DNA-Binding Proteins, GATA1 Transcription Factor, Gene Regulatory Networks, Humans, Hydroxylation, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, MDS1 and EVI1 Complex Locus Protein, Mutation, Myeloid Cells, Phenotype, Proto-Oncogene Proteins, Proto-Oncogenes, Transcription Factors

<p>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 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.</p>

Alternate JournalCancer Cell
PubMed ID21130701
PubMed Central IDPMC4105845
Grant ListR01 CA173636 / CA / NCI NIH HHS / United States
U54 CA143798 / CA / NCI NIH HHS / United States
CA 114737 / CA / NCI NIH HHS / United States
U10 CA021115 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
U54CA143798-01 / CA / NCI NIH HHS / United States
R01 HL082950 / HL / NHLBI NIH HHS / United States
R01 CA105463 / CA / NCI NIH HHS / United States
CA21115 / CA / NCI NIH HHS / United States
U24 CA114737 / CA / NCI NIH HHS / United States