β adrenergic signaling regulates hematopoietic stem and progenitor cell commitment and therapy sensitivity in multiple myeloma

• Authors: Remya Nair, Emory University; Vimal Subramaniam, Loyola University; Benjamin Barwick, Emory University; Vikas Gupta, Emory University; Shannon M Matulis, Emory University; Sagar Lonial, Emory University; Lawrence Boise, Emory University; Ajay Nooka, Emory University; Kuzhali Muthumalaiappan, Loyola University; Mala Shanmugam, Emory University
• Journal Title: Haematologica
• Volume: Volume 107, Number 9
• Publisher: Ferrata Storti Foundation | 2022-09-01, Pages 2223-2231
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3324/haematol.2022.280907
• Subjects: Health Sciences, Oncology
• Keywords: Multiple myeloma (MM)

Abstract

Multiple myeloma (MM) development is dependent upon critical interactions with the bone marrow (BM) niche.1 The contribution of catecholamines and adrenergic signaling from the highly innervated BM niche2 to MM development is under-explored. MM patients demonstrate an elevated conserved transcriptional response to adversity (CTRA), indicative of stress that correlates with poor survival.3 A retrospective study evaluating the effects of the non-selective b adrenergic receptor (AR) blocker propranolol in immunomodulatory drug-treated MM found propranolol to improve progression-free survival (PFS) and overall survival (OS).4 MM patients exhibit reduced megakaryocyte–erythrocyte progenitors (MEP) and increased monocytic myeloid-derived suppressor cells (MDSC) (CD14+HLADRlow) in the BM, suggestive of increased myeloid bias.5 Introduction of MM precursor monoclonal gammopathy of undetermined significance (MGUS) cells into humanized IL-6 MIS(KI)TRG6 mice promotes progression to MM, suggesting the sufficiency of extrinsic BM niche elements in fostering MM development.6 Consistent with this, administration of propranolol in MM patients undergoing hematopoietic stem cell transplant (HSCT) demonstrates a significant reduction of not only the CTRA response, but also marked reductions in myeloid lineage bias.3 How targeting adrenergic signaling regulates hematopoietic stem and progenitor cell (HSPC) commitment in MM remains poorly understood. Our study provides mechanistic rationale for the application of propranolol to resolve both microenvironmental and MM-specific tumor promoting biology.