@article{83ad6813849146dfba273ec3c1aeb6c7,
title = "Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation",
abstract = "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.",
author = "Figueroa, {Maria E.} and Omar Abdel-Wahab and Chao Lu and Ward, {Patrick S.} and Jay Patel and Alan Shih and Yushan Li and Neha Bhagwat and Aparna Vasanthakumar and Fernandez, {Hugo F.} and Tallman, {Martin S.} and Zhuoxin Sun and Kristy Wolniak and Peeters, {Justine K.} and Wei Liu and Choe, {Sung E.} and Fantin, {Valeria R.} and Elisabeth Paietta and Bob L{\"o}wenberg and Licht, {Jonathan D.} and Godley, {Lucy A.} and Ruud Delwel and Valk, {Peter J.M.} and Thompson, {Craig B.} and Levine, {Ross L.} and Ari Melnick",
note = "Funding Information: M.E.F. is funded by a Leukemia and Lymphoma Society Special Fellow award. A.M. is funded by a Leukemia and Lymphoma Society SCOR and TRP award, and is a Burroughs Wellcome Clinical Translational Scholar and Scholar of the Leukemia and Lymphoma Society. A.M. and M.E.F. are also supported by the Sackler Center for Biomedical and Physical Sciences. J.D.L. is funded by NIH grant R01 HL082950. C.B.T., C.L., and P.S.W. are supported in part by grants from the NCI and NIH. P.S.W. is also supported in part by the University of Pennsylvania Medical Scientist Training Program. This work was supported in part by U54CA143798-01 from the National Cancer Institute (to R.L.L.) and by a grant from the Starr Cancer Consortium (to R.L.L. and A.M.). R.L.L. is an Early Career Award Recipient of the Howard Hughes Medical Institute and is a Geoffrey Beene Junior Faculty Chair at Memorial Sloan-Kettering Cancer Center. E.P. is supported by NCI CA21115 and CA 114737. We would like to thank Adriana Heguy and Igor Dolgalev for assistance with DNA resequencing, and also thank Hans-Guido Wendel and Dino Mavrakis for assistance with TET2 shRNA construction. We thank Justin Cross and Dan Zlotoff for technical help and Sachie Marubayashi for assistance with murine bone marrow studies. W.L., S.E.C., V.R.F., and C.B.T. are employees or consultants of Agios Pharmaceuticals and have financial interest in Agios. ",
year = "2010",
month = dec,
day = "14",
doi = "10.1016/j.ccr.2010.11.015",
language = "English (US)",
volume = "18",
pages = "553--567",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}
