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.
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: 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.
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Alan
authors.initials: A
authors.lastname: Tseng
authors.affiliation: 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.
authors.forename: Isabel
authors.initials: I
authors.lastname: Beerman
authors.affiliation: 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.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Elia
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Bendall
authors.affiliation: 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.
authors.forename: François
authors.initials: F
authors.lastname: Lemonnier
authors.affiliation: 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.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Kron
authors.affiliation: 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.
authors.forename: David W
authors.initials: DW
authors.lastname: Cescon
authors.affiliation: 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.
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.affiliation: 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.
authors.forename: Evan F
authors.initials: EF
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authors.affiliation: The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.affiliation: 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.
authors.forename: Aline C
authors.initials: AC
authors.lastname: Planello
authors.affiliation: 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.
authors.forename: Shu Yi
authors.initials: SY
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authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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authors.initials: AH
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authors.forename: Dana M
authors.initials: DM
authors.lastname: Larsen
authors.affiliation: 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.
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Snow
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: 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.
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.affiliation: 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.
authors.forename: Chiara
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authors.lastname: Gorrini
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Bassi
authors.affiliation: 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.
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.affiliation: 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.
authors.forename: Kiichi
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authors.lastname: Murakami
authors.affiliation: 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.
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.affiliation: 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.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Agios Pharmaceuticals, Cambridge, MA 02139, USA.
authors.forename: Kimberly
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authors.forename: Katharine E
authors.initials: KE
authors.lastname: Yen
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester LE1 9HN, UK; Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome 00133, Italy.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: Department of Pathology, Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Cimmino
authors.affiliation: Department of Pathology, Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Iannis
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authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: 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.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: De Carvalho
authors.affiliation: 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.
authors.forename: Mathieu
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authors.lastname: Lupien
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 00133, USA.
authors.forename: Derrick J
authors.initials: DJ
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authors.affiliation: The Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Garry P
authors.initials: GP
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authors.affiliation: 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.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Cairns
authors.affiliation: 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.
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mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases; D015536:Down-Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; C551914:Tet2 protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse