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 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

doi:10.1016/j.ccell.2016.05.018

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 F. 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

Istituto Dermopatico dell'Immacolata , IDI

Research output: Contribution to journal › Article › peer-review

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 language	English
Journal	Cancer Cell
DOIs	https://doi.org/10.1016/j.ccell.2016.05.018
Publication status	Accepted/In press - Oct 30 2015

ASJC Scopus subject areas

Medicine(all)
Oncology
Cell Biology
Cancer Research

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Inoue, S., Li, W. Y., Tseng, A., Beerman, I., Elia, A. J., Bendall, S. C., Lemonnier, F., Kron, K. J., Cescon, D. W., Hao, Z., Lind, E. F., Takayama, N., Planello, A. C., Shen, S. Y., Shih, A. H., Larsen, D. M., Li, Q., Snow, B. E., Wakeham, A., ... 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 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.

In: Cancer Cell, 30.10.2015.

Research output: Contribution to journal › Article › peer-review

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 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 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. / Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. In: Cancer Cell. 2015.

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title = "Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2",

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.",

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T1 - Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2

AU - Inoue, Satoshi

AU - Li, Wanda Y.

AU - Tseng, Alan

AU - Beerman, Isabel

AU - Elia, Andrew J.

AU - Bendall, Sean C.

AU - Lemonnier, François

AU - Kron, Ken J.

AU - Cescon, David W.

AU - Hao, Zhenyue

AU - Lind, Evan F.

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.

PY - 2015/10/30

Y1 - 2015/10/30

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AB - 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.

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