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Type: Artigo
Title: Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2
Author: Inoue, Satoshi
Y. Li, Wanda
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.
Mak, Tak W.
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
Subject: DNA
Country: Reino Unido
Editor: Springer Nature
Rights: Aberto
Identifier DOI: 10.1016/j.ccell.2016.05.018
Date Issue: 2016
Appears in Collections:FOP - Artigos e Outros Documentos

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