Abstract PR02: Dynamic epigenetic regulation of glioblastoma tumorigenicity through a LSD1-MYC-OLIG2 axis

摘要: Glioblastoma is one of the most devastating human cancers, with near-uniform fatality within two years diagnosis. Therapeutic failure thought to be related small subpopulation cells that exhibit properties self-renewal and tumorigenicity. Understanding how such subpopulations attain retain these remains a central question in oncology. One fundamental issue whether tumorigenicity exists static population elite or capacity stochastically acquired. To test models, we assayed single-cell subclones derived from long-terms passaged primary patient-derived xenograft (PDX) glioblastoma lines. Our findings were best described by hybrid model largely deterministic (elite) but opportunities for dynamic (stochastic) interchange between non-tumorigenic tumorigenic states. identify molecular determinants tumorigenicity, performed gene expression profiling subclones. Analysis data suggested property driven variation MYC expression, which turn regulates Olig2 neural stem cell marker. Ectopic conferred tumorigenicty silencing abolished vitro vivo multiple PDX GEMM models. Transition states was associated changes histone modification at locus mediated lysine-specific demethylase 1 (LSD1). The suggests critical LSD1-MYC-OLIG2 axis transition differing unveils novel framework therapeutic development. Citation Format: Clark Chen, David Kozono, Jie Li, Masayuki Nitta, Oltea Sampetrean, Kimberly Ng, Gonda, Deepa S. Kushwaha, Dmitry Merzon, Valya Ramakrishnan, Shan Zhu, Kaya Hiroko Matsui, Olivier Harismendy, Wei Hua, Ying Mao, Chang-Hyuk Kwon, Keith L. Ligon, Hideyuki Saya, Bob Carter, Donald P. Pizzo, Scott R. VandenBerg, Frank Furnari, Webster Cavenee. Dynamic epigenetic regulation through axis. [abstract]. In: Proceedings AACR Special Conference on Myc: From Biology Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR02.