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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.

SUBMITTER: Inoue S 

PROVIDER: S-EPMC5022794 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.

Inoue Satoshi S   Li Wanda Y WY   Tseng Alan A   Beerman Isabel I   Elia Andrew J AJ   Bendall Sean C SC   Lemonnier François F   Kron Ken J KJ   Cescon David W DW   Hao Zhenyue Z   Lind Evan F EF   Takayama Naoya N   Planello Aline C AC   Shen Shu Yi SY   Shih Alan H AH   Larsen Dana M DM   Li Qinxi Q   Snow Bryan E BE   Wakeham Andrew A   Haight Jillian J   Gorrini Chiara C   Bassi Christian C   Thu Kelsie L KL   Murakami Kiichi K   Elford Alisha R AR   Ueda Takeshi T   Straley Kimberly K   Yen Katharine E KE   Melino Gerry G   Cimmino Luisa L   Aifantis Iannis I   Levine Ross L RL   De Carvalho Daniel D DD   Lupien Mathieu M   Rossi Derrick J DJ   Nolan Garry P GP   Cairns Rob A RA   Mak Tak W TW  

Cancer cell 20160714 2

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. Mut  ...[more]

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