MTAP loss promotes stemness in glioblastoma and confers unique susceptibility to purine starvation

Landon J. Hansen, Ran Sun, Rui Yang, Simranjit X. Singh, Lee H. Chen, Christopher J. Pirozzi, Casey J. Moure, Carlee Hemphill, Austin B. Carpenter, Patrick Healy, Ryan C. Ruger, Chin Pu J. Chen, Paula K. Greer, Fangping Zhao, Ivan Spasojevic, Carole Grenier, Zhiqing Huang, Susan K. Murphy, Roger E. McLendon, Henry S. FriedmanAllan H. Friedman, James E. HerndonII, John H. Sampson, Stephen T. Keir, Darell D. Bigner, Hai Yan, Yiping He

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1/CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1/ CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in MTAP-null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133+ cells in MTAP-null GBMcan be effectively depleted by inhibition of de novo purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics.

Original languageEnglish
Pages (from-to)3383-3394
Number of pages12
JournalCancer Research
Volume79
Issue number13
DOIs
StatePublished - 2019
Externally publishedYes

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