Abstract
Resistance to targeted therapies remains a major challenge in acute myeloid leukemia (AML). In FLT3-internal tandem duplication (FLT3-ITD) AML, FLT3 inhibitors such as quizartinib improve outcomes, but resistance limits long-term efficacy. While genetic resistance mechanisms are well characterized, the role of the bone marrow microenvironment remains unclear. We investigated how a pro-inflammatory microenvironment influences FLT3 inhibitor resistance and identified IFNγ as a key driver. IFNγ signaling activates STAT1, which in turn upregulates AXL, allowing leukemia cells to survive despite FLT3 inhibition. Knockdown, genomic degron tagging, and overexpression cell models confirmed STAT1 and AXL roles as mediators of resistance. Finally, analysis of IFNγ signaling and resistance in patient-derived AML blasts revealed variable sensitivity, suggesting the presence of additional compensatory mechanisms. These findings reveal IFNγ signaling as a mechanism of resistance, highlighting a potential therapeutic vulnerability in FLT3-mutated AML.