Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2 Journal Article

   


Authors: Inoue, S.; Li, W. Y.; Tseng, A.; Beerman, I.; Elia, A. J.; Bendall, S. C.; Lemonnier, F.; Kron, K. J.; Cescon, D. W.; Hao, Z.; Lind, E. F.; Takayama, N.; Planello, A. C.; Shen, S. Y.; Shih, A. H.; Larsen, D. M.; Li, Q.; Snow, B. E.; Wakeham, A.; Haight, J.; Gorrini, C.; Bassi, C.; Thu, K. L.; Murakami, K.; Elford, A. R.; Ueda, T.; Straley, K.; Yen, K. E.; Melino, G.; Cimmino, L.; Aifantis, I.; Levine, R. L.; De Carvalho, D. D.; Lupien, M.; Rossi, D. J.; Nolan, G. P.; Cairns, R. A.; Mak, T. W.
Article 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. © 2016 Elsevier Inc.
Journal Title: Cancer Cell
Volume: 30
Issue: 2
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2016-08-08
Start Page: 337
End Page: 348
Language: English
DOI: 10.1016/j.ccell.2016.05.018
PROVIDER: scopus
PMCID: PMC5022794
PUBMED: 27424808
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-84978828293&partnerID=40&md5=69d8ce7605321a1cd6210875b37f1c9c
Notes: Article -- Export Date: 1 November 2016 -- Source: Scopus
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MSK Authors
  1. Alan H Shih
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  2. Ross Levine
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