GSE126933
Combinatorial inhibition of Notch and FLT3 exerts synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia
we observed synergistic cytotoxic effects, preferentially reducing cell proliferation and inducing apoptosis in FLT3/ITD+ AML cell lines and in primary AML cells. Furthermore, the combination of FLT3-TKI and GSI eradicated leukemic cells and prolonged survival in a FLT3/ITD+ patient derived xenograft (PDX) AML model. Mechanistically, decreased expression of CXCR3 that lead to down-regulated ERK signaling was partially responsible for the observed synergy. Our findings suggest that combined therapies of FLT3-TKIs with GSI may be exploited as a potential therapeutic strategy to treat FLT3/ITD+ AML. Overall design: Analysis of FLT3/ITD+ AML cell lines (MV4-11 and MOLM13) treated with DMSO, 2.5nM AC220, 25uM DAPT or 2.5nM AC220 plus 25uM DAPT (Combo). The combination of AC220 plus DAPT AC220 exerts synergistic cytotoxic effects. Results provide insight into the synergism of FLT3/ITD+ AML cells from combined treatment.