3111 – LOSS OF A 7Q GENE, CUX1, DISRUPTS EPIGENETIC-DRIVEN DNA REPAIR AND CAUSES THERAPY-RELATED MYELOID NEOPLASM

Abstract

Therapy-related myeloid neoplasms (t-MN) are a high-risk, late effect in cancer survivors with poorly understood pathogenesis. It has been postulated that hematopoietic stem and progenitor cells (HSPCs) harboring mutations are selected for by cytotoxic exposures and transform. Here, we elucidate this model in the context of deficiency of CUX1, a transcription factor encoded on chromosome 7q. We report that CUX1 has a critical, early role in the DNA repair process in HSPCs. Mechanistically, CUX1 recruits the histone methyltransferase EHMT2 to DNA breaks to promote H3K27me3 deposition, phospho-ATM retention, subsequent γH2AX foci formation and propagation, and ultimately 53BP1 recruitment. Despite significant unrepaired DNA damage sustained in CUX1-deficient murine HSPCs after cytotoxic exposures, they continue to proliferate and expand, mimicking clonal hematopoiesis in patients post-chemotherapy. As a consequence, preexisting CUX1 deficiency predisposes mice to highly penetrant and rapidly fatal therapy-related erythroleukemias. These findings establish the importance of epigenetic regulation of DNA repair and position CUX1 as a gatekeeper in myeloid transformation.