AI Article Synopsis
- Homozygous deletion of the MTAP gene is common in glioblastoma (GBM) and leads to significant epigenetic changes, including hypomethylation of pathways linked to cancer stem cells.
- Loss of MTAP increases the formation of glioma stem-like cells (GSCs) that express higher levels of CD133 and are associated with a worse prognosis for GBM patients.
- Targeting purine synthesis may effectively reduce the prevalence of these CD133-positive cells in MTAP-deficient GBM, providing a potential therapeutic approach.
Article Abstract
Homozygous deletion of methylthioadenosine phosphorylase () 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 /CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of /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 -null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133 cells in -null GBM can be effectively depleted by inhibition of 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810595 | PMC |
| http://dx.doi.org/10.1158/0008-5472.CAN-18-1010 | DOI Listing |
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