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

Satoshi Inoue, Wanda Y. Li, Alan Tseng, Isabel Beerman, Andrew J. Elia, Sean C. Bendall, François Lemonnier, Ken J. Kron, David W. Cescon, Zhenyue Hao, Evan Lind, Naoya Takayama, Aline C. Planello, Shu Yi Shen, Alan H. Shih, Dana M. Larsen, Qinxi Li, Bryan E. Snow, Andrew Wakeham, Jillian HaightChiara 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

Research output: Contribution to journalArticle

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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. Although strong evidence supports that IDH1 mutants act by inhibiting TET2 in hematological malignancies, there are clear clinical differences between mutations of these genes. Inoue et al. show that mutant IDH1 decreases ATM independent of TET2, leading to impaired DNA repair and reduced hematopoietic stem cells.

Original languageEnglish (US)
JournalCancer Cell
DOIs
StateAccepted/In press - Oct 30 2015
Externally publishedYes

Fingerprint

Isocitrate Dehydrogenase
DNA Repair
DNA Damage
Down-Regulation
Genes
Hematopoietic Stem Cells
Acute Myeloid Leukemia
Mutation
Hematologic Neoplasms
DNA Methylation
Knockout Mice
Histones
Methylation
Leukemia

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Inoue, S., Li, W. Y., Tseng, A., Beerman, I., Elia, A. J., Bendall, S. C., ... Mak, T. W. (Accepted/In press). Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. Cancer Cell. https://doi.org/10.1016/j.ccell.2016.05.018

Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. / Inoue, Satoshi; Li, Wanda Y.; Tseng, Alan; Beerman, Isabel; Elia, Andrew J.; Bendall, Sean C.; Lemonnier, François; Kron, Ken J.; Cescon, David W.; Hao, Zhenyue; Lind, Evan; 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.

In: Cancer Cell, 30.10.2015.

Research output: Contribution to journalArticle

Inoue, S, Li, WY, Tseng, A, Beerman, I, Elia, AJ, Bendall, SC, Lemonnier, F, Kron, KJ, Cescon, DW, Hao, Z, Lind, E, 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 2015, 'Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2', Cancer Cell. https://doi.org/10.1016/j.ccell.2016.05.018
Inoue, Satoshi ; Li, Wanda Y. ; Tseng, Alan ; Beerman, Isabel ; Elia, Andrew J. ; Bendall, Sean C. ; Lemonnier, François ; Kron, Ken J. ; Cescon, David W. ; Hao, Zhenyue ; Lind, Evan ; 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. / Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. In: Cancer Cell. 2015.
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AU - Li, Wanda Y.

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AU - Elia, Andrew J.

AU - Bendall, Sean C.

AU - Lemonnier, François

AU - Kron, Ken J.

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AU - Takayama, Naoya

AU - Planello, Aline C.

AU - Shen, Shu Yi

AU - Shih, Alan H.

AU - Larsen, Dana M.

AU - Li, Qinxi

AU - Snow, Bryan E.

AU - Wakeham, Andrew

AU - Haight, Jillian

AU - Gorrini, Chiara

AU - Bassi, Christian

AU - Thu, Kelsie L.

AU - Murakami, Kiichi

AU - Elford, Alisha R.

AU - Ueda, Takeshi

AU - Straley, Kimberly

AU - Yen, Katharine E.

AU - Melino, Gerry

AU - Cimmino, Luisa

AU - Aifantis, Iannis

AU - Levine, Ross L.

AU - De Carvalho, Daniel D.

AU - Lupien, Mathieu

AU - Rossi, Derrick J.

AU - Nolan, Garry P.

AU - Cairns, Rob A.

AU - Mak, Tak W.

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