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Oncogenic signaling regulation of the mutant TERT promoter


Telomerase activation counteracts senescence and death-inducing telomere erosion caused by uncontrolled proliferation in cancer. Proliferation is highly correlated with telomerase activity across cancer types, suggesting there may be a mechanism linking these cancer hallmarks. In two of the major classes of adult diffuse glioma, high grade glioblastoma and low grade oligodendroglioma, telomerase reverse transcriptase promoter (TERTp) mutations are a predominant alteration underlying telomerase reactivation through recruitment of GA-binding protein (GABP). Very little is known about the mechanisms connecting drivers of proliferation to telomere maintenance and mutant TERTp regulation particularly in glioma. Epidermal growth factor receptor (EGFR) is commonly amplified in glioblastoma driving cell proliferation. EGFR amplification and TERTp mutations are frequent and significantly co-occur in glioblastoma. Oligodendroglioma lack EGFR amplification, but commonly rely on CIC mutations which modulate signaling downstream of receptor tyrosine kinase signaling. To determine if these two signaling pathways are functionally connected to mutant TERTp regulation in glioma, we combined analyses of copy number, mRNA, and protein data from primary tumor tissue with clinical pharmacologic treatments and genetic perturbations in cell lines and patient-derived cultures. From these data, we demonstrate that proliferation arrest lowers TERT expression in a GABP-dependent manner. We elucidate a proliferation-to-immortality pathway from EGFR to increased expression from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and subsequent GABP upregulation. We demonstrate the phenotypic consequences of EGFR-AMPK on promoting telomerase activity and telomere length. These results implicate GABP as a direct link between proliferation signals and telomerase reactivation that is specific to TERTp mutant glioblastoma. In oligodendroglioma, we demonstrate that CIC inactivation upregulates TERT from the mutant TERTp through E24 transformation-specific (ETS) factors other than GABP, showing that mechanisms driving proliferation can simultaneously upregulate the mutant TERTp in a cancer-type specific manner.

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