Abstract
Abstract High-grade glioma is a highly aggressive form of brain cancer associated with a poor prognosis. Recently, we identified that mesenchymal glioma stem cells (Mes GSCs) of HGG are linked to radiation resistance and proneural (PN) GSCs acquire Mes identity via radiation treatment. Here we performed a combined kinome-wide RNA interference screen with genome wide expression analysis to identify kinase-encoding genes that are essential for mesenchymal identity of GSCs. Through this stepwise screening with patient-derived GSC samples, we identified the serine/threonine kinase MLK4 as a key regulator for Mes GSC survival and cell cycle progression in vitro and tumor initiation and propagation in vivo. In addition, overexpression of MLK4 promotes, while both its gene-specific shRNA and pharmacological inhibition attenuate, proneural-mesenchymal transformation (PMT) of GSCs. In patient-derived GSCs, expression of MLK4 protein positively correlated with endogenous EGFRvIII expression and the in vivo growth of mouse xenografts derived from glioma cells with EGFRvIII expression was prominently inhibited by MLK4 knockdown. MLK4-overexpressing PN GSCs acquired radiation resistance, while MLK4 elimination by shRNA radiosensitized Mes GSCs. Patients with a higher MLK4 expression showed reduced survival in CD44-high populations. Collectively, these data indicate that MLK4 as a plausible target for therapy against Mes GBM as well as post-irradiation PN GBM. Citation Format: Kim Sunghak, Rosenstiel-Goidts Violaine, Shi-Yuan Cheng, Nakano Ichiro. Serine/threonine kinase MLK4 is a master regulator for proneural-mesenchymal transformation of glioma stem cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B72. doi:10.1158/1538-7445.CHTME14-B72
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