Targeting bone marrow mesenchymal stromal cell–derived IL-6 to overcome acute myeloid leukemia chemoresistance

In acute myeloid leukemia (AML), elevated interleukin 6 (IL-6) levels in the bone marrow (BM) are linked to poor prognosis. However, the mechanisms driving this elevation and its role in chemoresistance remain unclear. Using the Prrx1-Cre system, we selectively deleted Il6 in BM mesenchymal stromal cells (MSCs) and established an AML mouse model. Our results show that MSCs are a major source of IL-6 in AML BM. Importantly, Il6 deletion in MSCs reduced oxidative phosphorylation (OXPHOS) activity in AML cells, slowed disease progression, and enhanced chemosensitivity to cytarabine (Ara-C). Similarly, the OXPHOS inhibitor IACS-010759 improved chemosensitivity in AML mice. Exogenous recombinant IL-6 reversed the chemosensitivity gains from Il6 deletion, confirming its role in chemoresistance. We further demonstrated that Il6 absence in MSCs inhibits mitochondria transfer to AML cells, dampening OXPHOS and enhancing Ara-C efficacy. In summary, our study underscores the critical role of Il6 from MSCs in AML progression and chemoresistance. Targeting IL-6 in MSCs may offer a promising therapeutic strategy for AML. This trial was registered at www.clinicaltrials.gov as #NCT06486350.