@article{8aa052ebf6e44cc5ad850087610f14ba,
title = "Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2",
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.",
author = "Satoshi Inoue and Li, {Wanda Y.} and Alan Tseng and Isabel Beerman and Elia, {Andrew J.} and Bendall, {Sean C.} and Fran{\c c}ois Lemonnier and Kron, {Ken J.} and Cescon, {David W.} and Zhenyue Hao and Lind, {Evan F.} and Naoya Takayama and Planello, {Aline C.} and Shen, {Shu Yi} and Shih, {Alan H.} and Larsen, {Dana M.} and Qinxi Li and Snow, {Bryan E.} and Andrew Wakeham and Jillian Haight and Chiara Gorrini and Christian Bassi and Thu, {Kelsie L.} and Kiichi Murakami and Elford, {Alisha R.} and Takeshi Ueda and Kimberly Straley and Yen, {Katharine E.} and Gerry Melino and Luisa Cimmino and Iannis Aifantis and Levine, {Ross L.} and {De Carvalho}, {Daniel D.} and Mathieu Lupien and Rossi, {Derrick J.} and Nolan, {Garry P.} and Cairns, {Rob A.} and Mak, {Tak W.}",
note = "Funding Information: We are grateful to Drs. John E. Dick (Princess Margaret Cancer Centre), Atsushi Hirao (University of Kanazawa), and all members of the Mak laboratory for their advice. We also appreciate the assistance of Ms. Irene Ng and the staff members of the flow cytometer facility, genotyping facility, and animal resource centre of the Princess Margaret Cancer Centre. Finally, we are grateful to Dr. Mary Saunders for scientific editing of the manuscript. This work was supported by grants to Drs. T.W.M. and R.A.C. from the Canadian Institutes of Health Research and the Leukemia and Lymphoma Society. K.E.Y. is an employee of and has an ownership interest in Agios Pharmaceuticals. Funding Information: We are grateful to Drs. John E. Dick (Princess Margaret Cancer Centre), Atsushi Hirao (University of Kanazawa), and all members of the Mak laboratory for their advice. We also appreciate the assistance of Ms. Irene Ng and the staff members of the flow cytometer facility, genotyping facility, and animal resource centre of the Princess Margaret Cancer Centre. Finally, we are grateful to Dr. Mary Saunders for scientific editing of the manuscript. This work was supported by grants to Drs. T.W.M. and R.A.C. from the Canadian Institutes of Health Research and the Leukemia and Lymphoma Society . K.E.Y. is an employee of and has an ownership interest in Agios Pharmaceuticals . Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = aug,
day = "8",
doi = "10.1016/j.ccell.2016.05.018",
language = "English (US)",
volume = "30",
pages = "337--348",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}