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<p>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<sub>cγ1</sub> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • 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,
  • Jesús San-Miguel,
  • Borja Saez,
  • José A. Martinez-Climent,
  • Isabel A. Calvo,
  • David Gomez-Cabrero,
  • Felipe Prosper

摘要

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.