Inhibition of Ephrin B2 Reverse Signaling Suppresses Multiple Myeloma Pathogenesis

Bone marrow vascular endothelial cells (BM ECs) regulate multiple myeloma (MM) pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating MM. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote MM growth, revealing overexpression of the Receptor Tyrosine Kinases, EphB1 and EphB4, in MM - supportive ECs. Expression of Ephrin B2 (EFNB2), the binding partner for EphB1 and EphB4, was significantly increased in MM cells. Silencing EphB1 or EphB4 in ECs suppressed MM growth in co-culture. Similarly, loss of EFNB2 in MM cells blocked MM proliferation and survival in vitro, abrogated MM engraftment in immune-deficient mice, and increased MM sensitivity to chemotherapy. Administration of an EFNB2-targeted single chain variable fragment also suppressed MM growth in vivo. In contrast, overexpression of EFNB2 in MM cells increased STAT5 activation, increased MM cell survival and proliferation, and decreased MM sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in MM cells increased MM cell death and sensitivity to chemotherapy and abolished MM growth in vivo. Complementary analysis of MM patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls MM pathogenesis and can be therapeutically targeted to improve MM outcomes.