Synthetic lethal targeting ofTET2-mutant hematopoietic stem and progenitor cells by XPO1 inhibitors

Abstract

AbstractTET2inactivating mutations serve as initiating genetic lesions in the transformation of hematopoietic stem and progenitor cells (HSPCs). In this study, we analyzed known drugs in zebrafish embryos for their abilities to selectively killtet2-mutant HSPCsin vivo, and we found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively killtet2-mutant HSPCs. In serial replating colony assays, these small molecules were selectively active in killing murineTet2-deficient Lineage-, Sca1+, Kit+ (LSK) cells, and alsoTET2-inactivated human acute myeloid leukemia (AML) cells. Selective killing ofTET2-mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased γH2AX expression. The finding thatTET2loss renders HSPCs and AML cells selectively susceptible to cell death induced by XPO1 inhibitors provides preclinical evidence of selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment ofTET2-mutant hematopoietic malignancies and to suppress clonal expansion in age-relatedTET2-mutant clonal hematopoiesis.