Wnt Pathway Contributes to the Protection of Acute Lymphoblastic Leukemia Cells by Bone Marrow Stromal Cells and May Be a Therapeutic Target

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and one of the most common cancers in adults. Although most children with ALL can be cured, approximately 60% of adults with ALL develop drug resistance or experience relapse and cannot be cured with traditional chemotherapy. One possible reason that treatment fails to eradicate ALL cells is that residual leukemia cells are protected by various components of the bone marrow microenvironment, such as marrow stromal cells (MSCs). To evaluate the effects of MSCs on ALL cell survival and response to chemotherapy, we co-cultured ALL cells with human or murine MSCs. We found that both human and murine MSCs protected human ALL cell lines and primary ALL cells from spontaneous and Ara-C-induced apoptosis. MSCs also modulated the cell cycle and increased ALL cell proliferation. Specifically, we found that Wnt signaling activation contributed to MSC-mediated drug resistance. In contrast, blocking the Wnt pathway led to decreased ALL cell viability. Chemotherapy plus the -catenin inhibitor XAV939 resulted in a decreased tumor burden and improved overall survival in an ALL mouse model compared with chemotherapy alone. Our data demonstrate that targeting the Wnt pathway may represent an innovative approach to the treatment of ALL.

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