Multiplex gene editing models of del(7q) reveal combined and loss drives clonal expansion and drug resistance.

Loss of all or part of chromosome 7 [-7/del(7q)] is recurrent in myeloid neoplasms and associated with a poor response to chemotherapy. Chromosome 7-encoded genes driving drug resistance and the consequences of combinatorial 7q tumor suppressor gene loss have remained unclear, the latter question largely because of the challenges of modeling aneuploidy. Here, we use in silico data mining to uncover 7q genes involved in chemotherapy resistance. We establish murine models of del(7q) clonal hematopoiesis and drug resistance with multiplex CRISPR-Cas9 (CRISPR-associated protein 9)-mediated inactivation of 4 genes, , , , and . Postgenotoxic exposure, combined deficiency of and preferentially promotes clonal myeloid expansion in vivo, with compounding defects in DNA damage recognition and repair. Human acute myeloid leukemia cell lines similarly illustrate central roles for and loss in survival and DNA damage resolution after chemotherapy exposure. Transcriptome analysis reveals combined and loss recapitulates gene signatures of -7 patients and defective DNA damage response pathways, to a greater extent than single gene loss. This work reveals a genetic interaction between and , and sheds light on how -7/del(7q) contributes to leukemogenesis and drug resistance characteristic of these adverse-risk neoplasms. These data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple gene drives pathogenesis. Furthermore, our CRISPR-based approach may serve as a framework for interrogating other recurrent aneuploid events in cancer.