PTPS-15
ATRX LOSS PROMOTES TUMOR GROWTH AND IMPAIRS NON-HOMOLOGOUS END JOINING DNA REPAIR IN GLIOMA Free

Glioblastoma (GBM) remains one of the most difficult tumors to treat. ATRX is a histone chaperone protein that is mutated primarily in pediatric patients with GBM and younger adults with secondary GBM. Here, using the SB transposase system, we describe the first animal model of ATRX-deficient GBM. Notably, loss of ATRX significantly reduced median survival (p = 0.0032), uncovering a tumor suppressive effect of ATRX in GBM. As well, ATRX loss leads to genetic instability in mouse GBM, increasing rates of microsatellite instability and promoting alternate lengthening of telomeres (ALT). To correlate this genetic instability with human data, we retrieved and integrated genome-wide data of pediatric and adult glioma from multiple sequencing platforms. Our analysis of this data confirms that ATRX mutation is associated with increased somatic mutation rate at the sequence, but not at the chromosomal (structural) level in human glioma. Importantly, in our experimental model, we show that loss of ATRX results in impairment of non-homologous end joining (NHEJ) activity and loss of NHEJ pathway protein immuno-staining. In concordance with a NHEJ defect, treatment of ATRX-deficient tumor cells shows a higher sensitivity to DNA damaging agents that induce double-stranded DNA breaks, including irinotecan, topotecan, and irradiation. These data establish a previously unrecognized role for ATRX loss leading to impaired NHEJ in glioma, thus uncovering a therapeutic target for ATRX-mutated glioma. We also show that ATRX loss promotes GBM progression and enhances response to therapy. We propose that ATRX loss leads to a genetically unstable tumor, which is more aggressive when left untreated, but is more responsive to double-stranded DNA-damaging agents, ultimately resulting in improved overall survival. Supported by St. Baldrick's Fellowship and Alex's Lemonade Stand /Northwest Mutual Young Investigator Award to CK, NIH/NINDS grants to AM, MGC and PRL, and NHS grants to CJ, AM and JFS.