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MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Publication ,  Journal Article
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; Yan, H ...
Published in: Cancer Res
July 1, 2019

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2019

Volume

79

Issue

13

Start / End Page

3383 / 3394

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Survival Rate
  • Purines
  • Purine-Nucleoside Phosphorylase
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplastic Stem Cells
  • Mice
  • Humans
 

Citation

APA
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MLA
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Hansen, L. J., Sun, R., Yang, R., Singh, S. X., Chen, L. H., Pirozzi, C. J., … He, Y. (2019). MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation. Cancer Res, 79(13), 3383–3394. https://doi.org/10.1158/0008-5472.CAN-18-1010
Hansen, Landon J., Ran Sun, Rui Yang, Simranjit X. Singh, Lee H. Chen, Christopher J. Pirozzi, Casey J. Moure, et al. “MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.Cancer Res 79, no. 13 (July 1, 2019): 3383–94. https://doi.org/10.1158/0008-5472.CAN-18-1010.
Hansen LJ, Sun R, Yang R, Singh SX, Chen LH, Pirozzi CJ, et al. MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation. Cancer Res. 2019 Jul 1;79(13):3383–94.
Hansen, Landon J., et al. “MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.Cancer Res, vol. 79, no. 13, July 2019, pp. 3383–94. Pubmed, doi:10.1158/0008-5472.CAN-18-1010.
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. MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation. Cancer Res. 2019 Jul 1;79(13):3383–3394.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2019

Volume

79

Issue

13

Start / End Page

3383 / 3394

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Survival Rate
  • Purines
  • Purine-Nucleoside Phosphorylase
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplastic Stem Cells
  • Mice
  • Humans