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

TitleMutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2
Authors
Issue Date2016
Citation
Cancer Cell, 2016, v. 30, n. 2, p. 337-348 How to Cite?
Abstract© 2016 Elsevier Inc. 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.
Persistent Identifierhttp://hdl.handle.net/10722/292953
ISSN
2020 Impact Factor: 31.743
2020 SCImago Journal Rankings: 13.035
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorInoue, Satoshi-
dc.contributor.authorLi, Wanda Y.-
dc.contributor.authorTseng, Alan-
dc.contributor.authorBeerman, Isabel-
dc.contributor.authorElia, Andrew J.-
dc.contributor.authorBendall, Sean C.-
dc.contributor.authorLemonnier, François-
dc.contributor.authorKron, Ken J.-
dc.contributor.authorCescon, David W.-
dc.contributor.authorHao, Zhenyue-
dc.contributor.authorLind, Evan F.-
dc.contributor.authorTakayama, Naoya-
dc.contributor.authorPlanello, Aline C.-
dc.contributor.authorShen, Shu Yi-
dc.contributor.authorShih, Alan H.-
dc.contributor.authorLarsen, Dana M.-
dc.contributor.authorLi, Qinxi-
dc.contributor.authorSnow, Bryan E.-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorHaight, Jillian-
dc.contributor.authorGorrini, Chiara-
dc.contributor.authorBassi, Christian-
dc.contributor.authorThu, Kelsie L.-
dc.contributor.authorMurakami, Kiichi-
dc.contributor.authorElford, Alisha R.-
dc.contributor.authorUeda, Takeshi-
dc.contributor.authorStraley, Kimberly-
dc.contributor.authorYen, Katharine E.-
dc.contributor.authorMelino, Gerry-
dc.contributor.authorCimmino, Luisa-
dc.contributor.authorAifantis, Iannis-
dc.contributor.authorLevine, Ross L.-
dc.contributor.authorDe Carvalho, Daniel D.-
dc.contributor.authorLupien, Mathieu-
dc.contributor.authorRossi, Derrick J.-
dc.contributor.authorNolan, Garry P.-
dc.contributor.authorCairns, Rob A.-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:57:34Z-
dc.date.available2020-11-17T14:57:34Z-
dc.date.issued2016-
dc.identifier.citationCancer Cell, 2016, v. 30, n. 2, p. 337-348-
dc.identifier.issn1535-6108-
dc.identifier.urihttp://hdl.handle.net/10722/292953-
dc.description.abstract© 2016 Elsevier Inc. 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.-
dc.languageeng-
dc.relation.ispartofCancer Cell-
dc.titleMutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.ccell.2016.05.018-
dc.identifier.pmid27424808-
dc.identifier.pmcidPMC5022794-
dc.identifier.scopuseid_2-s2.0-84978828293-
dc.identifier.volume30-
dc.identifier.issue2-
dc.identifier.spage337-
dc.identifier.epage348-
dc.identifier.eissn1878-3686-
dc.identifier.isiWOS:000381282200015-
dc.identifier.issnl1535-6108-

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