Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression: MULTIPLE MYELOMA, GAMMOPATHIES

Gabriel Alvares Borges; Marta Diaz-delCastillo; Angelo J. Guilatco; Bilal Mohamad El-Masri; Fatima A. Mustapha; Michael T. Gundesen; Maja Hinge; Thomas Lund; Nadine Abdallah; Linda B. Baughn; Ming Xu; Anne Gingery; Tamar Tchkonia; James L. Kirkland; Taxiarchis Kourelis; Matthew T. Drake; Thomas Levin Andersen; Megan M. Weivoda

doi:10.1038/s41375-025-02572-z

Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression: MULTIPLE MYELOMA, GAMMOPATHIES

Gabriel Alvares Borges, Marta Diaz-delCastillo, Angelo J. Guilatco, Bilal Mohamad El-Masri, Fatima A. Mustapha, Michael T. Gundesen, Maja Hinge, Thomas Lund, Nadine Abdallah, Linda B. Baughn, Ming Xu, Anne Gingery, Tamar Tchkonia, James L. Kirkland, Taxiarchis Kourelis, Matthew T. Drake, Thomas Levin Andersen^*, Megan M. Weivoda^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Multiple myeloma (MM) is a plasma cell (PC) malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). MGUS and SMM PCs exhibit the same primary oncogenic abnormalities as MM but lack the end-organ damage that defines proliferative disease, suggesting that clonal PCs in these precursor conditions could exhibit senescence or senescence-like growth arrest. Herein we identified monoclonal gammopathy patient-derived PCs that exhibit senescence features and found that senescent PCs were significantly increased in MGUS patients compared to SMM or MM. Spatial analysis of senescent PCs in stable MGUS and SMM patient biopsies demonstrated the activation of local paracrine senescence in the bone marrow microenvironment. Stable MGUS and SMM patients also exhibited disease-specific senescence-associated secretory phenotype (SASP) signatures that significantly correlated with PC burden and clonal antibody. In contrast, progressing MGUS, SMM, and new MM patients lacked local paracrine senescence responses and robust activation of disease specific SASP signatures. Overall, these data suggest that failure to activate tumor-specific paracrine senescence responses is key to disease progression in monoclonal gammopathies.

Original language	English
Article number	4827
Journal	Leukemia
ISSN	0887-6924
DOIs	https://doi.org/10.1038/s41375-025-02572-z
Publication status	E-pub / Early view - 2025

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Borges, G. A., Diaz-delCastillo, M., Guilatco, A. J., El-Masri, B. M., Mustapha, F. A., Gundesen, M. T., Hinge, M., Lund, T., Abdallah, N., Baughn, L. B., Xu, M., Gingery, A., Tchkonia, T., Kirkland, J. L., Kourelis, T., Drake, M. T., Andersen, T. L., & Weivoda, M. M. (2025). Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression: MULTIPLE MYELOMA, GAMMOPATHIES. Leukemia, Article 4827. Advance online publication. https://doi.org/10.1038/s41375-025-02572-z

@article{a9c7f5750236431c92e8472fdd85e815,

title = "Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression: MULTIPLE MYELOMA, GAMMOPATHIES",

abstract = "Multiple myeloma (MM) is a plasma cell (PC) malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). MGUS and SMM PCs exhibit the same primary oncogenic abnormalities as MM but lack the end-organ damage that defines proliferative disease, suggesting that clonal PCs in these precursor conditions could exhibit senescence or senescence-like growth arrest. Herein we identified monoclonal gammopathy patient-derived PCs that exhibit senescence features and found that senescent PCs were significantly increased in MGUS patients compared to SMM or MM. Spatial analysis of senescent PCs in stable MGUS and SMM patient biopsies demonstrated the activation of local paracrine senescence in the bone marrow microenvironment. Stable MGUS and SMM patients also exhibited disease-specific senescence-associated secretory phenotype (SASP) signatures that significantly correlated with PC burden and clonal antibody. In contrast, progressing MGUS, SMM, and new MM patients lacked local paracrine senescence responses and robust activation of disease specific SASP signatures. Overall, these data suggest that failure to activate tumor-specific paracrine senescence responses is key to disease progression in monoclonal gammopathies.",

author = "Borges, {Gabriel Alvares} and Marta Diaz-delCastillo and Guilatco, {Angelo J.} and El-Masri, {Bilal Mohamad} and Mustapha, {Fatima A.} and Gundesen, {Michael T.} and Maja Hinge and Thomas Lund and Nadine Abdallah and Baughn, {Linda B.} and Ming Xu and Anne Gingery and Tamar Tchkonia and Kirkland, {James L.} and Taxiarchis Kourelis and Drake, {Matthew T.} and Andersen, {Thomas Levin} and Weivoda, {Megan M.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41375-025-02572-z",

language = "English",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

}

Borges, GA, Diaz-delCastillo, M, Guilatco, AJ, El-Masri, BM, Mustapha, FA, Gundesen, MT, Hinge, M, Lund, T, Abdallah, N, Baughn, LB, Xu, M, Gingery, A, Tchkonia, T, Kirkland, JL, Kourelis, T, Drake, MT, Andersen, TL & Weivoda, MM 2025, 'Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression: MULTIPLE MYELOMA, GAMMOPATHIES', Leukemia. https://doi.org/10.1038/s41375-025-02572-z

Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression: MULTIPLE MYELOMA, GAMMOPATHIES. / Borges, Gabriel Alvares; Diaz-delCastillo, Marta; Guilatco, Angelo J. et al.
In: Leukemia, 2025.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression

T2 - MULTIPLE MYELOMA, GAMMOPATHIES

AU - Borges, Gabriel Alvares

AU - Diaz-delCastillo, Marta

AU - Guilatco, Angelo J.

AU - El-Masri, Bilal Mohamad

AU - Mustapha, Fatima A.

AU - Gundesen, Michael T.

AU - Hinge, Maja

AU - Lund, Thomas

AU - Abdallah, Nadine

AU - Baughn, Linda B.

AU - Xu, Ming

AU - Gingery, Anne

AU - Tchkonia, Tamar

AU - Kirkland, James L.

AU - Kourelis, Taxiarchis

AU - Drake, Matthew T.

AU - Andersen, Thomas Levin

AU - Weivoda, Megan M.

PY - 2025

Y1 - 2025

N2 - Multiple myeloma (MM) is a plasma cell (PC) malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). MGUS and SMM PCs exhibit the same primary oncogenic abnormalities as MM but lack the end-organ damage that defines proliferative disease, suggesting that clonal PCs in these precursor conditions could exhibit senescence or senescence-like growth arrest. Herein we identified monoclonal gammopathy patient-derived PCs that exhibit senescence features and found that senescent PCs were significantly increased in MGUS patients compared to SMM or MM. Spatial analysis of senescent PCs in stable MGUS and SMM patient biopsies demonstrated the activation of local paracrine senescence in the bone marrow microenvironment. Stable MGUS and SMM patients also exhibited disease-specific senescence-associated secretory phenotype (SASP) signatures that significantly correlated with PC burden and clonal antibody. In contrast, progressing MGUS, SMM, and new MM patients lacked local paracrine senescence responses and robust activation of disease specific SASP signatures. Overall, these data suggest that failure to activate tumor-specific paracrine senescence responses is key to disease progression in monoclonal gammopathies.

AB - Multiple myeloma (MM) is a plasma cell (PC) malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). MGUS and SMM PCs exhibit the same primary oncogenic abnormalities as MM but lack the end-organ damage that defines proliferative disease, suggesting that clonal PCs in these precursor conditions could exhibit senescence or senescence-like growth arrest. Herein we identified monoclonal gammopathy patient-derived PCs that exhibit senescence features and found that senescent PCs were significantly increased in MGUS patients compared to SMM or MM. Spatial analysis of senescent PCs in stable MGUS and SMM patient biopsies demonstrated the activation of local paracrine senescence in the bone marrow microenvironment. Stable MGUS and SMM patients also exhibited disease-specific senescence-associated secretory phenotype (SASP) signatures that significantly correlated with PC burden and clonal antibody. In contrast, progressing MGUS, SMM, and new MM patients lacked local paracrine senescence responses and robust activation of disease specific SASP signatures. Overall, these data suggest that failure to activate tumor-specific paracrine senescence responses is key to disease progression in monoclonal gammopathies.

UR - http://www.scopus.com/inward/record.url?scp=105001514735&partnerID=8YFLogxK

U2 - 10.1038/s41375-025-02572-z

DO - 10.1038/s41375-025-02572-z

M3 - Journal article

C2 - 40164720

AN - SCOPUS:105001514735

SN - 0887-6924

JO - Leukemia

JF - Leukemia

M1 - 4827

ER -

Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression: MULTIPLE MYELOMA, GAMMOPATHIES

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