Project Term: July 1, 2022 - June 30, 2025
Multiple myeloma (MM) relies on the bone marrow (BM) niche to progress to refractory disease. We found that beta blockers alter BM niche elements fostering MM growth and also reduce MM cell survival. Our objective is to elucidate the cellular and metabolic basis of how beta adrenergic signals impact the BM niche and MM progression. Knowledge of the prophylactic and therapeutic utility of beta blockers in MM will unravel new means to target neural niche remodeling fueling this fatal malignancy.
Multiple myeloma (MM) is a fatal plasma cell malignancy accounting for 10% of all hematologic malignancies with 12,410 estimated deaths in the US in 2021. MM cells hijack the bone marrow (BM) niche creating anemia, osteolytic lesions, calcification and a therapy resistant reservoir of residual MM. MM relies on the bone marrow niche to progress to refractory disease. The BM niche is highly innervated supporting neural regulation of MM growth. Neural signals impact cell function through beta adrenergic receptors. Retrospective analysis suggests beta adrenergic receptor (beta-AR) blockers like propranolol (FDA approved medication used to treat high blood pressure), improve progression free survival (PFS) and overall survival (OS) of immunomodulatory drug-treated MM patients; the mechanistic basis of which is unknown.
Our evaluation of the NCT01454297 1150 MM patient trial demonstrates elevated beta-AR2, suggesting that MM cells can be responsive to beta-AR mediated signals. Common myeloid progenitors (CMPs) are precursors to several pro-metastatic bone marrow niche cell types. The proteins v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B transcription factor (MAFB) and globin transcription factor 1 (GATA1) are central regulators of myeloid vs. erythroid lineage commitment in CMPs in the BM. Increased myeloid commitment fosters MM growth. We previously determined that the beta blocker propranolol shifts BM myeloid-erythroid commitment towards megakaryocyte erythrocyte progenitors (MEPs) by altering v-maf MAFB expression in CMPs in a mouse scald burn injury model and in human burn patients. Like our findings in burn patients treated with the beta blocker, we found that propranolol alters BM hematopoietic niche elements fostering MM growth and also reduces MM cell survival. Our objective is to elucidate the cellular and metabolic basis of how beta blockers impact the BM niche and MM progression.
Our findings can have immediate translational impact by unravelling the mechanistic basis for the anti-MM effects of beta blockers to support the application of FDA approved beta blockers for MM therapy. Knowledge of the prophylactic and therapeutic utility of beta blockers in MM will unravel new means to target neural niche remodeling fueling this fatal malignancy.