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Stromal and Endothelial Transcriptional Changes during progression from MGUS to Myeloma and after Treatment Response | bioRxiv

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Stromal and Endothelial Transcriptional Changes during progression from MGUS to Myeloma and after Treatment Response

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https://www.biorxiv.org/content/10.1101/2024.04.24.589777v4

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The role of the bone marrow non-immune microenvironment (BME) in the transition from monoclonal gammopathy of undetermined significance (MGUS) into clinically active multiple myeloma (MM) remains incompletely defined. To address this, we performed single-cell RNA sequencing (scRNA-seq) of non-hematopoietic BME cells and MM cells from two genetically engineered mouse models ![Graphic][1]</img> and ![Graphic][2]</img> that recapitulate MGUS to MM progression. Our analysis revealed distinct transcriptional trajectories in endothelial cells (EC) and mesenchymal stem cells (MSC), uncovering stage-specific BME–PC interactions that shape disease progression. EC adopted a stress phenotype during MGUS and transitioned into a proliferative, angiogenic state in MM. In parallel, MSC exhibited impaired differentiation capacity and an inflammatory transcriptional program that intensified during MM development. Notably, an interferon (IFN)-associated MM signature was detected in both EC and MSC from the ![Graphic][3]</img> model but was absent in the more aggressive ![Graphic][4]</img> model. We further show that treatment with bortezomib, lenalidomide, and dexamethasone (VRd) remodeled the BME by suppressing IFN-driven transcriptional programs, promoting an adaptive stress response in EC, and restoring osteogenic potential in MSC—shifting the niche toward a less tumor-permissive state. Importantly, elements of the IFN-related MM signature were validated in MSCs from newly diagnosed patients across the MGUS-to-MM spectrum, supporting the translational relevance of our findings. Together, these data define dynamic, targetable alterations in the non-immune BME during myeloma progression and highlight potential therapeutic strategies. KEY POINTS ### 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. 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. [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif

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Stromal and Endothelial Transcriptional Changes during progression from MGUS to Myeloma and after Treatment Response

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The role of the bone marrow non-immune microenvironment (BME) in the transition from monoclonal gammopathy of undetermined significance (MGUS) into clinically active multiple myeloma (MM) remains incompletely defined. To address this, we performed single-cell RNA sequencing (scRNA-seq) of non-hematopoietic BME cells and MM cells from two genetically engineered mouse models ![Graphic][1]</img> and ![Graphic][2]</img> that recapitulate MGUS to MM progression. Our analysis revealed distinct transcriptional trajectories in endothelial cells (EC) and mesenchymal stem cells (MSC), uncovering stage-specific BME–PC interactions that shape disease progression. EC adopted a stress phenotype during MGUS and transitioned into a proliferative, angiogenic state in MM. In parallel, MSC exhibited impaired differentiation capacity and an inflammatory transcriptional program that intensified during MM development. Notably, an interferon (IFN)-associated MM signature was detected in both EC and MSC from the ![Graphic][3]</img> model but was absent in the more aggressive ![Graphic][4]</img> model. We further show that treatment with bortezomib, lenalidomide, and dexamethasone (VRd) remodeled the BME by suppressing IFN-driven transcriptional programs, promoting an adaptive stress response in EC, and restoring osteogenic potential in MSC—shifting the niche toward a less tumor-permissive state. Importantly, elements of the IFN-related MM signature were validated in MSCs from newly diagnosed patients across the MGUS-to-MM spectrum, supporting the translational relevance of our findings. Together, these data define dynamic, targetable alterations in the non-immune BME during myeloma progression and highlight potential therapeutic strategies. KEY POINTS ### 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. 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. [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif

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