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

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Date
2016-08
ICR Author
Gorrini, Chiara
Author
Inoue, S
Li, WY
Tseng, A
Beerman, I
Elia, AJ
Bendall, SC
Lemonnier, F
Kron, KJ
Cescon, DW
Hao, Z
Lind, EF
Takayama, N
Planello, AC
Shen, SY
Shih, AH
Larsen, DM
Li, Q
Snow, BE
Wakeham, A
Haight, J
Gorrini, C
Bassi, C
Thu, KL
Murakami, K
Elford, AR
Ueda, T
Straley, K
Yen, KE
Melino, G
Cimmino, L
Aifantis, I
Levine, RL
De Carvalho, DD
Lupien, M
Rossi, DJ
Nolan, GP
Cairns, RA
Mak, TW
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/4120
DOI
https://doi.org/10.1016/j.ccell.2016.05.018
Collections
  • Cancer Therapeutics
Subject
Hematopoietic Stem Cells
Animals
Humans
Mice
DNA Damage
Isocitrate Dehydrogenase
DNA-Binding Proteins
Proto-Oncogene Proteins
DNA Repair
Down-Regulation
Mutation
Ataxia Telangiectasia Mutated Proteins
Research team
Target Evaluation and Molecular Therapeutics
Language
eng
Date accepted
2016-05-31
License start date
2016-08
Citation
Cancer cell, 2016, 30 (2), pp. 337 - 348

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