BMSCs-AML cell interaction drives FLT3 inhibitor resistance through the NR2F2/COX-2/PGE2 Axis

Although FMS-like tyrosine kinase-3 (FLT3) inhibitors initially induce a favorable response in AML patients, their long-term efficacy is often limited by the development of resistance. Bone marrow stromal cells (BMSCs), a key component of AML bone marrow niche, support leukemia cell survival and drive drug resistance through multiple approaches like direct contact, cytokine secretion, and exosome release. BMSC-mediated AML resistance involves complex and heterogeneous mechanisms that vary depending on the drug type and the characteristics of the leukemic cells. Therefore, this study seeks to elucidate how BMSCs interact with FLT3-ITD-mutated AML cells to confer FLT3 inhibitor resistance, aiming to identifying potential therapeutic targets to overcome such resistance. We discovered that BMSCs co-cultured with leukemia cells exhibited elevated expression of COX-2 and its product PGE2. BMSC-derived PGE2 suppressed ferroptosis in AML cells by modulating fatty acid metabolism and enhancing the glutathione antioxidant system. Additionally, PGE2 activated the GSK3β/β-catenin signaling pathway, facilitating the nuclear translocation of β-catenin, which influenced the apoptotic rates of AML cells. Proinflammatory cytokines such as TNF-α and IL-1β secreted by FLT3-ITD-mutated AML cells suppressed NR2F2 expression in BMSCs, leading to de-repression of COX-2 and subsequent PGE2 secretion, further amplifying this regulatory loop. Taken together, our findings reveal a novel mechanism whereby the NR2F2/COX-2/PGE2 axis modulates the sensitivity of AML cells to FLT3 inhibitors, and targeting this circuit may serve as an adjuvant therapy to improve FLT3 inhibitor efficacy.