Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

The role of the bone marrow microenvironment (BME) in the transition from monoclonal gammopathy of undetermined significance (MGUS) into clinically active multiple myeloma (MM) is not completely determined. To address this issue, we performed single-cell RNA sequencing (scRNA-seq) of non-hematopoietic BME cells as well as plasma cells (PC) from two genetically engineered mouse models of MM termed BI _cγ1 and MI _cγ1 that recapitulate the progression of MGUS into MM. Our results identify distinct transcriptional dynamics between endothelial cells (EC) and mesenchymal stem cells (MSC). While EC acquire a stress state during MGUS, a proliferating and angiogenic profile characterizes MM. On the other hand, MSC compromised their differentiation potential, exhibiting a more inflammatory profile that initiates from the MGUS stage. Interestingly, we identified an interferon (IFN)-related myeloma signature in malignant EC of the BI _cγ1 model, which is also expressed in MSC but not observed in the more aggressive MI _cγ1 model and can be identified in MSC from a subgroup of MM patients. The analysis of the EC and MSC interactions with malignant PC revealed stage-specific interactions that contribute to angiogenesis, immunomodulation, and MM extravasation. Finally, the translational relevance of our results in humans was confirmed on MSC from newly diagnosed patients with monoclonal gammopathies at different stages of the disease. In summary, these results show a remodeling of the non-hematopoietic BME in MM progression, providing potential targets at the tumor-niche interface that may hold clinical significance and complement existing immunotherapies.

Abstract Figure

KEY POINTS

• EC stress pre-vascular state in MGUS, shifts to angiogenic in MM, while MSC early transcriptional changes in MGUS persist in overt MM.

• Identification of a myeloma-specific IFN signature in the non-hematopoietic BME that could define a subgroup of MM patients.