Chemotherapy‐driven expression of <scp>WNT</scp> ligands in bone marrow stromal cells contributes to chemoresistance in acute lymphoblastic leukaemia

Despite recent advances, treatment outcomes for adults with acute lymphoblastic leukaemia (ALL) remain poor. Although patients often exhibit an initial favourable response to chemotherapy, with substantial clearance of tumour cells, most patients eventually relapse. This indicates the persistence of a chemoresistant ALL subpopulation capable of driving disease regeneration. Growing evidence implicates interactions between leukaemia cells and the bone marrow (BM) niche in this process. Our findings show that BM-derived mesenchymal stem cells (MSCs) and adipocytes (BMAds) promote chemotherapy resistance in ALL cells via activation of the wingless-related integration site (WNT) signalling pathway. Chemotherapy-treated co-cultures of MSCs/BMAds and ALL cells exhibited upregulation of several WNT ligands in the stromal compartment. Notably, pharmacological inhibition of WNT signalling abrogated the stromal-mediated chemoprotection and enhanced ALL cell apoptosis in vitro. In vivo, WNT inhibition in a p185^BCR-ABLArf^-/- B-ALL mouse model sensitised leukaemia cells to chemotherapy, delaying relapse and extending survival. Collectively, these results support the therapeutic potential of WNT inhibitors as a strategy to block the cross-talk between the BM stroma and leukaemic cells and reduce ALL chemoresistance.