Our long-term research goal is to develop novel therapies against chemotherapy resistance in multiple myeloma (MM). The goal of the proposed project, which is to elucidate the way in which chemotherapy resistance is maintained in MM cells, is essential to attaining our long-term research goal because it will provide an improved understanding of the mechanisms that could be therapeutically targeted to reduce or prevent chemotherapy resistance in this disease. Our preliminary studies revealed that adipocytes (ADs) are a dominant type of bone marrow (BM) stromal cells (BMSCs) in the BM of MM patients. These studies showed for the first time that the BM of patients with relapsed MM contained remarkably more ADs than the BM of patients with non-relapsed disease did and that MM cells surround and contact ADs. We found that co-culture with ADs protected MM cells against chemotherapy-induced apoptosis and that the AD-secreted adipokine chemerin is a novel factor that mediates ADs' protection of MM cells against chemotherapy. In addition, co-culture with MM cells enhanced AD formation and ADs' production of chemerin, and the addition of an antibody against the Wnt inhibitor dickkopf-1 (DKK-1) abrogated such effects. An analysis of microarray data revealed that the proteins upregulated in MM cells co-cultured with ADs included autophagy proteins such as Beclin-1 and signaling kinases such as AMPK, which are involved in MM cell proliferation and cell death. The array data also revealed that the proteins upregulated in ADs co-cultured with MM cells included AD-related proteins and transcriptional factors such as PPAR2, which are involved in AD differentiation and ADs' production of adipokines. On the basis of these novel findings, we hypothesize that MM-secreted DKK-1 enhances AD differentiation and chemerin secretion and that AD-secreted chemerin in turn protects MM cells against chemotherapy-induced apoptosis. In the proposed study, we will determine whether AD-secreted chemerin induces autophagy, thereby inhibiting MM cell apoptosis, by activating AMPK and inhibiting mTOR. We will also determine whether MM-secreted DKK-1 activates PPAR, thereby enhancing AD differentiation and ADs' production of chemerin, by inhibiting Wnt/ß-catenin signaling. The knowledge gained with the successful completion of the proposed work will improve the care of MM patients by informing the development of new strategies to combat relapsed or refractory disease.