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Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.
Inoue, Satoshi; Li, Wanda Y; Tseng, Alan; Beerman, Isabel; Elia, Andrew J; Bendall, Sean C; Lemonnier, François; Kron, Ken J; Cescon, David W; Hao, Zhenyue; Lind, Evan F; Takayama, Naoya; Planello, Aline C; Shen, Shu Yi; Shih, Alan H; Larsen, Dana M; Li, Qinxi; Snow, Bryan E; Wakeham, Andrew; Haight, Jillian; Gorrini, Chiara; Bassi, Christian; Thu, Kelsie L; Murakami, Kiichi; Elford, Alisha R; Ueda, Takeshi; Straley, Kimberly; Yen, Katharine E; Melino, Gerry; Cimmino, Luisa; Aifantis, Iannis; Levine, Ross L; De Carvalho, Daniel D; Lupien, Mathieu; Rossi, Derrick J; Nolan, Garry P; Cairns, Rob A; Mak, Tak W.
Affiliation
  • Inoue S; 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.
  • Li WY; 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.
  • Tseng A; 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
  • Beerman I; 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.
  • Elia AJ; 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.
  • Bendall SC; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Lemonnier F; 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.
  • Kron KJ; 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.
  • Cescon DW; 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.
  • Hao Z; 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.
  • Lind EF; 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.
  • Takayama N; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
  • Planello AC; 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, Brazi
  • Shen SY; 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.
  • Shih AH; Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Larsen DM; Mbed Pathology, Toronto, ON M5J 2H2, Canada.
  • Li Q; 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.
  • Snow BE; 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.
  • Wakeham A; 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.
  • Haight J; 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.
  • Gorrini C; 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.
  • Bassi C; 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.
  • Thu KL; 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.
  • Murakami K; 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.
  • Elford AR; 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.
  • Ueda T; 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.
  • Straley K; Agios Pharmaceuticals, Cambridge, MA 02139, USA.
  • Yen KE; Agios Pharmaceuticals, Cambridge, MA 02139, USA.
  • Melino G; Medical Research Council, Toxicology Unit, Leicester LE1 9HN, UK; Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome 00133, Italy.
  • Cimmino L; Department of Pathology, Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
  • Aifantis I; Department of Pathology, Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
  • Levine RL; Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • De Carvalho DD; 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.
  • Lupien M; 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.
  • Rossi DJ; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 00133, USA.
  • Nolan GP; The Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Cairns RA; 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.
  • Mak TW; 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
Cancer Cell ; 30(2): 337-348, 2016 08 08.
Article in En | MEDLINE | ID: mdl-27424808
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Damage / Hematopoietic Stem Cells / Proto-Oncogene Proteins / DNA-Binding Proteins / DNA Repair / Ataxia Telangiectasia Mutated Proteins / Isocitrate Dehydrogenase Type of study: Diagnostic_studies Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2016 Type: Article Affiliation country: Canada
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Damage / Hematopoietic Stem Cells / Proto-Oncogene Proteins / DNA-Binding Proteins / DNA Repair / Ataxia Telangiectasia Mutated Proteins / Isocitrate Dehydrogenase Type of study: Diagnostic_studies Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2016 Type: Article Affiliation country: Canada