The current study demonstrated that a novel peptidic CXCR4 inhibitor, LY2510924, effectively disrupted the CXCL12/CXCR4 axis and reversed microenvironment-mediated resistance to the FLT3 inhibitor, quizartinib, mainly through downregulation of persistent MAPK activation, which enhanced the sensitivity of FLT3-ITD-AML cells to FLT3 inhibitors in vitro and in vivo. This evidence concerns the gene FLT3 and acute myeloid leukemia.