Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma

We previously showed that macrophages (MFs) infiltrate the bone marrow (BM) of patients with myeloma and may play a role in drug resistance. This study analyzed chemokines expressed by myeloma BM that are responsible for recruiting monocytes to the tumor bed. We found that chemokines CCL3, CCL14, and CCL2 were highly expressed by myeloma and BM cells, and the levels of CCL14 and CCL3 in myeloma BM positively correlated with the percentage of BM-infiltrating MFs. In vitro, these chemokines were responsible for chemoattracting human monocytes to tumor sites and in vivo for M Phi infiltration into myeloma-bearing BM in the 5TGM1 mouse model. Surprisingly, we also found that these chemokines stimulated M Phi in vitro proliferation induced by myeloma cells and in vivo in a human myeloma xenograft SCID mouse model. The chemokines also activated normal MF polarization and differentiation into myeloma-associated M Phi s. Western blot analysis revealed that these chemokines promoted growth and survival signaling in M Phi s via activating the PI3K/Akt and ERK MAPK pathways and c-myc expression. Thus, this study provides novel insight into the mechanism of M Phi infiltration of BM and also potential targets for improving the efficacy of chemotherapy in myeloma.