Annexin II Interactions with the Annexin II Receptor Enhance Multiple Myeloma Cell Adhesion and Growth In the Bone Marrow Microenvironment

Abstract 130

Multiple myeloma (MM) is an incurable B-cell malignancy that develops in the bone marrow. The marrow microenvironment plays a critical role in supporting homing, lodging, and growth of MM cells by activating signaling pathways in both MM and bone marrow stromal cells (BMSC). Recently, we identified that annexin II (AXII) is involved in prostate cancer cell lodgment to the bone marrow as well as mobilization of prostate cancer cells to the peripheral blood. AXII expressed on stromal cells supports prostate cancer cell lodgment via the annexin II receptor (AXIIR) on prostate cancer cells. We hypothesized that MM cells use a similar mechanism to lodge and grow in the bone marrow. We demonstrated using bio-AXII, that MM cell lines and primary MM cells from 8 MM patients express the AXIIR protein. In addition, MM cells adhered significantly better to BMSC from wild-type mice than from AXII^−/− mice. Knockdown of AXIIR by siRNA in MM.1S and ANBL.6 MM cells resulted in decreased AXII binding and decreased adherence of MM cells to KM101 stromal cells and BMSC from wild-type mice. Furthermore, the adhesion of MM.1S^siCon and MM.1S^siAXIIR cells to AXII^−/− BMSC was similar indicating that AXII produced by MM cells does not act in an autocrine manner on attachment. Therefore, our studies indicate the importance of the interaction of AXII on BMSC with AXIIR on MM cells in adhesion. Our studies also revealed a role for AXIIR signaling on MM cell growth. We found that soluble AXII was released by osteoclasts into their conditioned media and stimulated the growth of MM cells via ERK1/2 and AKT phosphorylation in MM cells. AXII stimulation of MM cell growth was blocked by AXII antibody or by blocking ERK1/2 and AKT phosphorylation. In contrast, endogenous AXII produced by MM.1S cells did not stimulate MM.1S cell growth suggesting that autocrine AXII/AXIIR signaling in MM.1S cells does not contribute to MM.1S cell growth. Taken together, these results suggest that AXII/AXIIR axis in the myeloma microenvironment plays an important role in MM cell adhesion and growth through production of AXII by BMSC and osteoclasts.