Proposed model of FLT3i-guided synthetic lethality triggered by PARP1i in FLT3(ITD)-positive AML cells. Synthetic lethality arises when a combination of deficiencies in the expression of 2 or more genes leads to cell death, whereas a deficiency in only 1 of these genes does not. FLT3i downregulates the expression of multiple genes involved in DSB repair causing HR and D-NHEJ deficiency in FLT3(ITD)-positive leukemia cells but not in normal counterparts. This effect causes PARP1i-triggered accumulation of toxic DSBs and synthetic lethality in leukemia cells, whereas normal cells are spared.