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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; Li
Wanda Y.; Tseng
Alan; Beerman
Isabel; Elia
Andrew J.; Bendall
Sean C.; Lemonnier
Francois; 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.; Wakeham
Andrew; Haight
Jillian; Gorrini
Chiara; Bassi
Christian; Thu
Kelsie L.; Murakami
Kiichi; Elford
Alisha R.; Ueda
Takeshi; Straley
Kimberly; Yen
Katharine E.; Melino
Gerry; Cimmino
Luisa; Aifantis
Iannis; Levine
Ross L.; De Carvalho
Daniel D.; Lupien
Mathieu; Rossi
Derrick J.; Nolan
Garry P.; Cairns
Rob A.; 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.
Editor: Cell Press
Citation: Cancer Cell. Cell Press, v. 30, p. 337 - 348, 2016.
Rights: fechado
Identifier DOI: 10.1016/j.ccell.2016.05.018
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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