Abstract 5598: Combined loss of the chromosome 7 genes CUX1 and EZH2 promotes chemotherapy resistance

Abstract

Abstract Monosomy 7 (-7) or del(7q) are recurrent in high-risk myeloid neoplasms, including up to 50% of myeloid neoplasms arising after prior exposure to chemotherapy and/or radiation. Although putative chromosome 7 tumor suppressor genes have been identified, the effects of combinatorial 7q gene loss remain unclear. A barrier to understanding the pathogenesis of -7/del(7q) is the challenge of modeling aneuploidy in animal models. To address this knowledge gap, we established an in vivo model of del(7q) clonal hematopoiesis and drug resistance using multiplex CRISPR-Cas9 to simultaneously target four 7q genes (Cux1, Ezh2, Kmt2c, and Kmt2e) in murine hematopoietic stem cells. After chemotherapy exposure, we observe significant myeloid expansion of clones edited for both Cux1 and Ezh2. Compared to the transcriptomes of control or single gene edited cells, Cux1;Ezh2-deficient cells fail to induce DNA damage response pathways after genotoxic stress. Cux1;Ezh2-deficient cells also display reduced deposition of γH2AX after DNA damage, as well as persistent, unrepaired DNA breaks, indicating perturbations to DNA damage recognition and repair. Collectively, our data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple genes drives drug resistance and disease development. This work reveals a genetic interaction between CUX1 and EZH2, and sheds light on how -7/del(7q) contributes to the development and inherent drug resistance characteristic of high-risk myeloid disease. Further, our CRISPR-based approach may serve as a framework for interrogating other recurrent aneuploid events in cancer. Citation Format: Matthew R. Jotte, Angela Stoddart, Tanner C. Martinez, Yuqing Xue, Molly K. Imgruet, Megan E. McNerney. Combined loss of the chromosome 7 genes CUX1 and EZH2 promotes chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5598.