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 journalArticle

73 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)337-348
Number of pages12
JournalCancer Cell
Volume30
Issue number2
DOIs
StatePublished - Aug 8 2016

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Inoue, S., Li, W. Y., Tseng, A., Beerman, I., Elia, A. J., Bendall, S. C., Lemonnier, F., Kron, K. J., Cescon, D. W., Hao, Z., Lind, E. F., Takayama, N., Planello, A. C., Shen, S. Y., Shih, A. H., Larsen, D. M., Li, Q., Snow, B. E., Wakeham, A., ... Mak, T. W. (2016). Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. Cancer Cell, 30(2), 337-348. https://doi.org/10.1016/j.ccell.2016.05.018