Stromal and endothelial transcriptional changes during progression from MGUS to myeloma and after treatment response
Abstract
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 MI cγ1 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.
Article Details
Authors (30)
Itziar Cenzano
Miguel Cócera
Marta Larrayoz
Lorea Campos-Dopazo
Sonia Sanz
Azari Bantan
Amaia Vilas-Zornoza
Patxi San-Martin
Paula Aguirre-Ruiz
Diego Alignani
Aitziber Lopez
Ignacio Sancho González
Javier Ruiz
Purificacion Ripalda-Cemborain
Marta Abengozar-Muela
Emma Muiños-López
Vincenzo Lagani
Jesper Tegner
Mikel Hernáez
Xabier Agirre
Benjamin Ebert
Bruno Paiva
Paula Rodriguez-Otero
Luis-Esteban Tamariz-Amador
Jesus San-Miguel
Borja Saez
José A. Martinez-Climent
Isabel A. Calvo
David Gomez-Cabrero
Felipe Prosper