A potential strategy to enhance multiple myeloma therapeutic efficacy

At the cellular level, MM is caused by the clonal expansion of antibody-producing plasma cells within the bone marrow. Abundant adipocytes within the bone marrow contribute to MM development and pathogenesis by participating in MM growth, mediating obesity-induced tumorigenesis, recruiting tumor cells to specific bone areas and regulating osteoclast and osteoblast differentiation and activity. Interestingly, bone marrow adipocytes also contribute to MM therapeutic resistance via inhibition of chemotherapy-induced tumor cell apoptosis. In an effort to better understand exactly how the adipocyte-rich bone marrow microenvironment induces MM drug resistance Jing Yang, PhD, associate professor of oncology, and her team explored the intracellular communication among key cellular machinery, MM cells and adipocytes using both murine models and MM patient samples. MM cells can program adipocytes to secrete distinct adipokines or cytokines that work against MM treatments by creating a bone marrow microenvironment that is more favorable for MM growth and survival. Apart from adipokines, adipocytes also secrete exosomes that play a role in tumor-stroma cellular communication as well as stroma-induced tumor drug resistance. These can carry non-coding RNA molecules, including long non-coding RNAs (LncRNAs) which can be transferred to another cell upon engulfment. Yang and her team tested the hypothesis that MM cells modulate LncRNA enrichment into adipocyte exosomes which when internalized into MM cells inhibit chemotherapy-induced apoptosis. They collected exosomes from MM patient adipocytes which protected MM cells from chemotherapy-induced apoptosis. Specifically, two LncRNAs (LOC606724 and SNHG1) were upregulated in MM cells post-exposure to adipocyte exosomes which correlated with worse patient outcomes. There is a balanced communication between MM cells and adipocytes in the bone marrow microenvironment which is regulated by the exosomal packaging of LncRNAs. Interestingly, LncRNAs regulate oncogenes and function in the pathogenesis of benign and malignant ailments. Using methyltransferase activity assays and dot blotting, Yang’s study was the first to demonstrate that methyltransferase like 7A (METTL7A) possesses RNA methyltransferase activity that participates in LncRNA m6A methylation and contributes to adipocyte-induced MM therapeutic resistance. Upon methylation, LncRNAs are packaged into exosomes. Yang also demonstrated that pharmaceutical or genetic depletion, using adipocyte-specific enhancer of zeste homolog 2 (EZH2) knockout mice, of EZH2 diminishes METTL7A protein methylation levels in MM-associated adipocytes thereby affecting LncRNA methylation and exosomal LncRNA packaging. Furthermore, Yang evaluated the effects of combination therapy of bortezomib with tazemetostat, a drug approved by the Food and Drug Administration for the treatment of follicular lymphoma on tumor growth. “In multiple myeloma, preclinical studies show that tazemetostat has a tumoricidal activity with additional therapeutic effect on multiple myeloma-associated bone disease through regulation of osteoblast differentiation and activity,” said Yang. “We confirmed that combining bortezomib with tazemetostat significantly reduces exosomal LncRNA levels in marrow adipocytes. Thus, our results may provide an additional mechanistic insight for improving the clinical efficacy of tazemetostat within the tumor microenvironment.” The important findings in this study improve our understanding of MM pathobiology and pinpoint the cycle between MM cells and adipocytes as a potential target for designing novel anti-MM therapeutic agents.