Mer receptor expression promotes multiple myeloma disease development via a cell-extrinsic mechanism

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the uncontrolled proliferation of bone marrow resident plasma cells (PCs). Two members of the TAM (TYRO3, AXL, and MER) receptor family have previously been implicated in distinct aspects of neoplastic PC biology. AXL expression in MM PCs has been associated with the induction of a dormant, noncycling state within the bone marrow, whereas expression of MER has been implicated in PC proliferation and survival. Here, the generation of single TAM receptor-expressing 5TGM1 murine MM cell lines enabled the individual functional assessment of the effects of Axl and Mer receptor expression on MM development. Axl expression did not affect proliferation, cell cycling, or stromal cell-induced dormancy in vitro. Development of 5TGM1 tumors in C57BL/KaLwRij mice was also unaltered by Axl expression. By contrast, Mer expression conferred an increase in cell proliferation to 5TGM1 cells in vitro and increased 5TGM1 tumor burden in C57BL/KaLwRij mice. The protumorigenic properties of Mer were only observed following intravenous cell delivery into mice with an intact adaptive immune system. Thus, Axl is neither necessary nor sufficient for the induction of MM cancer cell dormancy, whereas MER remains a promising target for therapeutic intervention in patients with MM.