Stromal and endothelial transcriptional changes during progression from MGUS to myeloma and after treatment response

Abstract

Progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is accompanied by profound remodeling of the bone marrow microenvironment (BME), yet the contribution of its non-immune compartment remains unclear. Using single-cell RNA sequencing in genetically engineered mouse models that recapitulate disease evolution, we transcriptionally profile endothelial cells (EC) and mesenchymal stem cells (MSC). EC adopt a stress-associated program at MGUS that precedes angiogenesis in MM, while MSC undergo early and sustained loss of differentiation capacity. We identify a coordinated interferon (IFN)-driven program across EC and MSC that defines MM in the BIcγ1 model but is absent in the more aggressive MIcγ1 model. Treatment with bortezomib, lenalidomide, and dexamethasone suppresses this IFN signature, promotes endothelial adaptation, and restores osteogenic potential in MSC. Validation in patient samples reveals enrichment of this IFN-signature across disease stages. These findings define dynamic and targetable alterations in the non-immune BME during myeloma progression.

Conflict of interest statement

Competing interests: A patent on the knowhow and experimental use of the BIcγ1 and MIcγ1 mouse models of MM has been licensed to MIMO Biosciences. J.A.M.-C. has received research funding from Roche-Genentech, Bristol Myers Squibb, Janssen, Regeneron, Priothera Pharmaceuticals, Palleon Pharmaceuticals, AstraZeneca, and K36 Therapeutics, and is founder and holds stock options of MIMO Biosciences. The authors declare no competing interests.

CITA DEL ARTÍCULO Nat Commun. 2026 Jun 23;17(1):7893. doi: 10.1038/s41467-026-74389-y.