Synthetic lethal targeting of TET2-mutant hematopoietic stem and progenitor cells by XPO1 inhibitors
Jing, C.; Prutsch, N.; He, S.; Zimmerman, M. W.; Landesman, Y.; Look, A. T. W.
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TET2 inactivating 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 kill tet2-mutant HSPCs in vivo, and we found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively kill tet2-mutant HSPCs. In serial replating colony assays, these small molecules were selectively active in killing murine Tet2-deficient Lineage-, Sca1+, Kit+ (LSK) cells, and also TET2-inactivated human acute myeloid leukemia (AML) cells. Selective killing of TET2-mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased {gamma}H2AX expression. The finding that TET2 loss 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 of TET2-mutant hematopoietic malignancies and to suppress clonal expansion in age-related TET2-mutant clonal hematopoiesis.
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