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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2016 Jul 19

PMID 27424808

Citations 119

Authors

Satoshi Inoue

Wanda Y Li

Alan Tseng

Isabel Beerman

Andrew J Elia

Sean C Bendall

Francois Lemonnier

Ken J Kron

David W Cescon

Zhenyue Hao

Evan F Lind

Naoya Takayama

Aline C Planello

Shu Yi Shen

Alan H Shih

Dana M Larsen

Qinxi Li

Bryan E Snow

Andrew Wakeham

Jillian Haight

Chiara Gorrini

Christian Bassi

Kelsie L Thu

Kiichi Murakami

Alisha R Elford

Takeshi Ueda

Kimberly Straley

Katharine E Yen

Gerry Melino

Luisa Cimmino

Iannis Aifantis

Ross L Levine

Daniel D De Carvalho

Mathieu Lupien

Derrick J Rossi

Garry P Nolan

Rob A Cairns

Tak W Mak

Affiliations

Soon will be listed here.

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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