| Literature DB >> 27424808 |
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.
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.Entities:
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Year: 2016 PMID： 27424808 PMCID： PMC5022794 DOI： 10.1016/j.ccell.2016.05.018
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743