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Cancer Cell. 2016 Aug 8;30(2):337-348. doi: 10.1016/j.ccell.2016.05.018. Epub 2016 Jul 14.

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

Author information

1
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
2
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 00133, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
4
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
6
The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
7
The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Morphology, Piracicaba Dental School, UNICAMP, Piracicaba, SP 13414-903, Brazil.
8
Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Mbed Pathology, Toronto, ON M5J 2H2, Canada.
10
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Disease Model Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
11
Agios Pharmaceuticals, Cambridge, MA 02139, USA.
12
Medical Research Council, Toxicology Unit, Leicester LE1 9HN, UK; Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome 00133, Italy.
13
Department of Pathology, Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
14
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 00133, USA.
15
The Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
16
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: tmak@uhnres.utoronto.ca.

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.

Comment in

PMID:
27424808
PMCID:
PMC5022794
DOI:
10.1016/j.ccell.2016.05.018
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Other authors declare that no conflicts of interest exist.

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