Runx2 deficiency in osteoblasts promotes myeloma resistance to bortezomib by increasing thrombospondin 1-mediated TGF-ß1 activation and suppression immunity in the bone marrow

Abstract Background: Multiple myeloma (MM) is a plasma cell malignancy that thrives in the bone marrow (BM). Although the proteasome inhibitor bortezomib (BTZ) is one of the most effective front-line chemotherapeutic drugs for MM, 15–20% of high-risk patients do not respond to this drug or become resistant to treatment. The mechanisms driving this chemoresistance remain unclear. Previous studies showed that the tumor microenvironment contributes to cancer chemoresistance. Our recent studies demonstrated that Runt-related transcription factor 2 (Runx2) deficiency in osteoblasts (OBs) creates a cytokine-rich and immunosuppressive microenvironment in the BM and promotes MM progression. However, the impact of Runx2 deficiency in OBs on the efficacy of BTZ in treatment of MM is still unknown. Methods: We assessed the effects of OB-Runx2 deficiency on the outcome of BTZ treatment in OB-Runx2 +/+ and OB-Runx2 -/- mouse models with MM using bioluminescence imaging, ELISA and flow cytometry. In addition, we used a co-culturing in vitro system to explore the mechanism of BTZ resistance and assessed this system by MTT assays and Western blot analysis. Results: We discovered that OB-Runx2 deficiency induces MM cells resistance to BTZ via the suppression of immunity and increased active TGF-β1 in the BM. We further demonstrated that depletion of myeloid-derived suppressor cells (MDSCs) by gemcitabine or inhibition of TGF-ß1 activity by SRI31277, a compound that blocks thrombospondin 1 (TSP1)-mediated TGF-ß1 activation, restores anti-tumor immunity in the BM and overcomes BTZ resistance induced by OB-Runx2 deficiency. In addition, SRI31277 also directly inhibits the activity of canonical (Smad2/3) and non-canonical (Erk1/2) signaling pathways of TGF-ß1 in 5TGM1-Luc MM cells and sensitizes MM cells to BTZ, resulting in increased apoptosis of MM cells. Conclusions: OB-Runx2 deficiency promotes BTZ resistance in MM cells through the regulations of MDSCs and TSP1-mediated TGF-ß1 activation in the BM. These data identify novel mechanisms of BTZ resistance in MM and suggest new strategies to overcome BTZ resistance in treatment of MM.