Age-related mesenchymal stromal cell senescence is associated with progression from MGUS to multiple myeloma.
Files
(Published version)
Date
2025
Authors
Plakhova, N.
Panagopoulos, V.
Cantley, M.D.
Trainor, L.J.
Hewett, D.R.
Clark, K.C.
Gardiner, J.
Yong, A.
Lee, C.
Horvath, N.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Leukemia, 2025; 39(6):1464-1475
Statement of Responsibility
Natalya Plakhova, Vasilios Panagopoulos, Melissa D. Cantley, Laura J. Trainor, Duncan R. Hewett, Kimberley C. Clark, Jo Gardiner, Angelina Yong, Cindy Lee, Noemi Horvath, Peter I. Croucher, Dimitrios Cakouros, Sheila A. Stewart, Stan Gronthos, Andrew C. W. Zannettino, Krzysztof M. Mrozik, and Kate Vandyke
Conference Name
Abstract
The risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) increases with advancing age, suggesting that progression may be influenced by age-related changes within the bone marrow (BM) microenvironment. We hypothesise that senescent mesenchymal stromal cells (MSCs), which accumulate in the BM with age, may contribute to MGUS progression to MM. Here, we show that, like BM MSCs from aged non-cancer controls, BM MSCs from both MM and MGUS patients exhibit a senescent phenotype characterised by enlarged, flattened morphology, increased β-galactosidase activity and CDKN2A expression, and decreased proliferation rate compared with BM MSCs from healthy young individuals. While coculture with BM MSCs suppresses the proliferative capacity of MM cell lines in vitro, induction of senescence via irradiation or replicative exhaustion in healthy MSCs relieves this suppression, compared with non-senescent MSCs. This may, in part, be attributable to upregulated expression of the BMP antagonist Gremlin1 in senescent MSCs, which facillitates MM cell proliferation. Notably, the risk of progression to MM was significantly elevated in MGUS patients with increased MSC senescence. Collectively, our data provide evidence that age-related accumulation of senescent MSCs may be a driver of MGUS to MM progression.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.