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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6680-6689
Number of pages10
JournalCancer Research
Volume76
Issue number22
DOIs
StatePublished - Nov 15 2016
Externally publishedYes

Fingerprint

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

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.

In: Cancer Research, Vol. 76, No. 22, 15.11.2016, p. 6680-6689.

Research output: Contribution to journalArticle

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, vol. 76, no. 22, pp. 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. In: Cancer Research. 2016 ; Vol. 76, No. 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.",
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AU - Chow, Tracy T.

AU - Wood, Matthew

AU - Jones, Lindsey

AU - Mazor, Tali

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AU - Perry, Arie

AU - Bell, Robert J.A.

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AU - Ronen, Sabrina M.

AU - Pieper, Russell O.

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