Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2

Satoshi Inoue, Wanda Y. Li, Alan Tseng, Isabel Beerman, Andrew J. Elia, Sean C. Bendall, François Lemonnier, Ken J. Kron, David W. Cescon, Zhenyue Hao, Evan F. Lind, Naoya Takayama, Aline C. Planello, Shu Yi Shen, Alan H. Shih, Dana M. Larsen, Qinxi Li, Bryan E. Snow, Andrew Wakeham, Jillian HaightChiara Gorrini, Christian Bassi, Kelsie L. Thu, Kiichi Murakami, Alisha R. Elford, Takeshi Ueda, Kimberly Straley, Katharine E. Yen, Gerry Melino, Luisa Cimmino, Iannis Aifantis, Ross L. Levine, Daniel D. De Carvalho, Mathieu Lupien, Derrick J. Rossi, Garry P. Nolan, Rob A. Cairns, Tak W. Mak

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between . IDH1- and . TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to . Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human . IDH1-mutated AML. These findings may have implications for treatment of . IDH-mutant leukemia. Although strong evidence supports that IDH1 mutants act by inhibiting TET2 in hematological malignancies, there are clear clinical differences between mutations of these genes. Inoue et al. show that mutant IDH1 decreases ATM independent of TET2, leading to impaired DNA repair and reduced hematopoietic stem cells.

Original languageEnglish
JournalCancer Cell
DOIs
Publication statusAccepted/In press - Oct 30 2015

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cell Biology
  • Cancer Research

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