Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process

Shigeo Ohba, Joydeep Mukherjee, Tor Christian Johannessen, Andrew Mancini, Tracy T. Chow, Matthew Wood, Lindsey Jones, Tali Mazor, Roxanne E. Marshall, Pavithra Viswanath, Kyle M. Walsh, Arie Perry, Robert J.A. Bell, Joanna J. Phillips, Joseph F. Costello, Sabrina M. Ronen, Russell O. Pieper

研究成果: Article

16 引用 (Scopus)

抄録

Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo. Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation.

元の言語English
ページ(範囲)6680-6689
ページ数10
ジャーナルCancer Research
76
発行部数22
DOI
出版物ステータスPublished - 15-11-2016

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Telomere
Mutation
Histones
Methylation
Telomerase
Population
Genes
Isocitrate Dehydrogenase
Glioma
Astrocytes
Lysine
Agar
Phenotype
Neoplasms
alpha-hydroxyglutarate

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Ohba, S., Mukherjee, J., Johannessen, T. C., Mancini, A., Chow, T. T., Wood, M., ... Pieper, R. O. (2016). Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process. Cancer Research, 76(22), 6680-6689. https://doi.org/10.1158/0008-5472.CAN-16-0696
Ohba, Shigeo ; Mukherjee, Joydeep ; Johannessen, Tor Christian ; Mancini, Andrew ; Chow, Tracy T. ; Wood, Matthew ; Jones, Lindsey ; Mazor, Tali ; Marshall, Roxanne E. ; Viswanath, Pavithra ; Walsh, Kyle M. ; Perry, Arie ; Bell, Robert J.A. ; Phillips, Joanna J. ; Costello, Joseph F. ; Ronen, Sabrina M. ; Pieper, Russell O. / Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process. :: Cancer Research. 2016 ; 巻 76, 番号 22. pp. 6680-6689.
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abstract = "Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo. Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation.",
author = "Shigeo Ohba and Joydeep Mukherjee and Johannessen, {Tor Christian} and Andrew Mancini and Chow, {Tracy T.} and Matthew Wood and Lindsey Jones and Tali Mazor and Marshall, {Roxanne E.} and Pavithra Viswanath and Walsh, {Kyle M.} and Arie Perry and Bell, {Robert J.A.} and Phillips, {Joanna J.} and Costello, {Joseph F.} and Ronen, {Sabrina M.} and Pieper, {Russell O.}",
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Ohba, S, Mukherjee, J, Johannessen, TC, Mancini, A, Chow, TT, Wood, M, Jones, L, Mazor, T, Marshall, RE, Viswanath, P, Walsh, KM, Perry, A, Bell, RJA, Phillips, JJ, Costello, JF, Ronen, SM & Pieper, RO 2016, 'Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process', Cancer Research, 巻. 76, 番号 22, pp. 6680-6689. https://doi.org/10.1158/0008-5472.CAN-16-0696

Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process. / Ohba, Shigeo; Mukherjee, Joydeep; Johannessen, Tor Christian; Mancini, Andrew; Chow, Tracy T.; Wood, Matthew; Jones, Lindsey; Mazor, Tali; Marshall, Roxanne E.; Viswanath, Pavithra; Walsh, Kyle M.; Perry, Arie; Bell, Robert J.A.; Phillips, Joanna J.; Costello, Joseph F.; Ronen, Sabrina M.; Pieper, Russell O.

:: Cancer Research, 巻 76, 番号 22, 15.11.2016, p. 6680-6689.

研究成果: Article

TY - JOUR

T1 - Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process

AU - Ohba, Shigeo

AU - Mukherjee, Joydeep

AU - Johannessen, Tor Christian

AU - Mancini, Andrew

AU - Chow, Tracy T.

AU - Wood, Matthew

AU - Jones, Lindsey

AU - Mazor, Tali

AU - Marshall, Roxanne E.

AU - Viswanath, Pavithra

AU - Walsh, Kyle M.

AU - Perry, Arie

AU - Bell, Robert J.A.

AU - Phillips, Joanna J.

AU - Costello, Joseph F.

AU - Ronen, Sabrina M.

AU - Pieper, Russell O.

PY - 2016/11/15

Y1 - 2016/11/15

N2 - Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo. Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation.

AB - Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo. Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation.

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