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

The role of the bone marrow (BM) microenvironment 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 BM non-hematopoietic microenvironment cells as well as plasma cells (PC) from two genetically engineered mouse models of MM termed BIcγ and MIcγ that recapitulate the progression of MGUS into MM. Our results identify distinct transcriptional dynamics between mesenchymal stem cells (MSC) and endothelial cells (EC). 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 BIcγ model, which is also expressed in MSC but not observed in the more aggressive MIcγ model and can be identified in MSC from a subgroup of MM patients. The analysis of the MSC and EC interactions with malignant plasma cells (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 PC neoplasias at different stages of the disease. In summary, these results show a remodeling of the non-hematopoietic BM microenvironment in MM progression, providing potential targets at the tumor-niche interface that may hold clinical significance and complement existing immunotherapies. ### Competing Interest Statement A patent on the knowhow and experimental use of the BIcγ1 and MIcγ1 mouse models of MM has been licensed to MIMO Biosciences. The authors declare no competing interests.