Runx2 Deficiency in Osteoblasts Promotes Myeloma Resistance to Bortezomib by Increasing TSP-1–Dependent TGFβ1 Activation and Suppressing Immunity in Bone Marrow

Abstract

Multiple myeloma is a plasma cell malignancy that thrives in the bone marrow (BM). The proteasome inhibitor bortezomib is one of the most effective first-line chemotherapeutic drugs for multiple myeloma; however, 15% to 20% of high-risk patients do not respond to or become resistant to this drug and the mechanisms of chemoresistance remain unclear. We previously demonstrated that multiple myeloma cells inhibit Runt-related transcription factor 2 (Runx2) in pre- and immature osteoblasts (OB), and that this OB-Runx2 deficiency induces a cytokine-rich and immunosuppressive microenvironment in the BM. In the current study, we assessed the impact of OB-Runx2 deficiency on the outcome of bortezomib treatment using OB-Runx2+/+ and OB-Runx2−/− mouse models of multiple myeloma. In vitro and in vivo experiments revealed that OB-Runx2 deficiency induces multiple myeloma cell resistance to bortezomib via the upregulation of immunosuppressive myeloid-derived suppressor cells (MDSCs), downregulation of cytotoxic T cells, and activation of TGFβ1 in the BM. In multiple myeloma tumor-bearing OB-Runx2−/− mice, treatment with SRI31277, an antagonist of thrombospondin-1 (TSP-1)–mediated TGFβ1 activation, reversed the BM immunosuppression and significantly reduced tumor burden. Furthermore, treatment with SRI31277 combined with bortezomib alleviated multiple myeloma cell resistance to bortezomib-induced apoptosis caused by OB-Runx2 deficiency in cocultured cells and produced a synergistic effect on tumor burden in OB-Runx2−/− mice. Depletion of MDSCs by 5-fluorouracil or gemcitabine similarly reversed the immunosuppressive effects and bortezomib resistance induced by OB-Runx2 deficiency in tumor-bearing mice, indicating the importance of the immune environment for drug resistance and suggesting new strategies to overcome bortezomib resistance in the treatment of multiple myeloma.

RUNX2 and Cancer

“…In prostate cancer, the increased expression of RUNX2 under nitric oxide conditions conferred resistance to docetaxel in LNCaP cells, and activation of the ERK-PI3K-AP1-RUNX2 axis was indicated [ 25 ]. In contrast to previous findings, a role for RUNX2 in alleviating drug resistance was reported: in multiple myeloma, a mouse model with specific RUNX2 deficiency in osteoblasts (RUNX2 −/− ) rendered multiple myeloma cells more resistant to bortezomib via thrombospondin-1-mediated TGFβ1 activation, whereas the malignancy and tumor burden were reversed by treatment with the antagonist SRI31277 [ 41 ].…”

RUNX2 prompts triple negative breast cancer drug resistance through TGF-β pathway regulating breast cancer stem cells

“…In our previous study, we uncovered that a transcription factor, RUNX2, also known as core-binding factor (cbf-α), is a molecule that is highly active in the development and differentiation of bone tissues and the development of various tumors, especially in breast cancer bone metastasis [ 13 , 14 ], and it also plays a regulatory role in chemoresistance in some tumors [ 15 , 16 ]. Rajnee Kanwal et al.…”