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 Haight; Chiara 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

doi:10.1016/j.ccell.2016.05.018

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

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

Authors

Satoshi Inoue¹, Wanda Y Li¹, Alan Tseng², Isabel Beerman³, Andrew J Elia¹, Sean C Bendall⁴, François Lemonnier¹, Ken J Kron⁵, David W Cescon¹, Zhenyue Hao¹, Evan F Lind¹, Naoya Takayama⁶, Aline C Planello⁷, Shu Yi Shen⁵, Alan H Shih⁸, Dana M Larsen⁹, Qinxi Li¹, Bryan E Snow¹, Andrew Wakeham¹, Jillian Haight¹, Chiara Gorrini¹, Christian Bassi¹, Kelsie L Thu¹, Kiichi Murakami¹, Alisha R Elford¹, Takeshi Ueda¹⁰, Kimberly Straley¹¹, Katharine E Yen¹¹, Gerry Melino¹², Luisa Cimmino¹³, Iannis Aifantis¹³, Ross L Levine⁸, Daniel D De Carvalho⁵, Mathieu Lupien⁵, Derrick J Rossi¹⁴, Garry P Nolan¹⁵, Rob A Cairns¹, Tak W Mak¹⁶

Affiliations

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.

MeSH terms

Animals
Ataxia Telangiectasia Mutated Proteins / genetics*
Ataxia Telangiectasia Mutated Proteins / metabolism
DNA Damage*
DNA Repair*
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Dioxygenases
Down-Regulation
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / enzymology*
Humans
Isocitrate Dehydrogenase / genetics*
Isocitrate Dehydrogenase / metabolism
Mice
Mutation
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism

Substances

DNA-Binding Proteins
Proto-Oncogene Proteins
Isocitrate Dehydrogenase
IDH1 protein, human
Dioxygenases
TET2 protein, human
Tet2 protein, mouse
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Atm protein, mouse

Abstract

MeSH terms

Substances

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