MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.
Journal Article (Journal Article)
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 GBM can 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. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.
Full Text
Duke Authors
- Bigner, Darell Doty
- Friedman, Allan Howard
- Friedman, Henry Seth
- He, Yiping
- Herndon II, James Emmett
- Keir, Stephen Thomas
- McLendon, Roger Edwin
- Murphy, Susan Kay
- Pirozzi, Christopher
- Sampson, John Howard
- Singh, Simranjit
- Yan, Hai
Cited Authors
- Hansen, LJ; Sun, R; Yang, R; Singh, SX; Chen, LH; Pirozzi, CJ; Moure, CJ; Hemphill, C; Carpenter, AB; Healy, P; Ruger, RC; Chen, C-PJ; Greer, PK; Zhao, F; Spasojevic, I; Grenier, C; Huang, Z; Murphy, SK; McLendon, RE; Friedman, HS; Friedman, AH; Herndon, JE; Sampson, JH; Keir, ST; Bigner, DD; Yan, H; He, Y
Published Date
- July 1, 2019
Published In
Volume / Issue
- 79 / 13
Start / End Page
- 3383 - 3394
PubMed ID
- 31040154
Pubmed Central ID
- PMC6810595
Electronic International Standard Serial Number (EISSN)
- 1538-7445
Digital Object Identifier (DOI)
- 10.1158/0008-5472.CAN-18-1010
Language
- eng
Conference Location
- United States