Plakhova Natalya, Panagopoulos Vasilios, Cantley Melissa D, Trainor Laura J, Hewett Duncan R, Clark Kimberley C, Gardiner Jo, Yong Angelina, Lee Cindy, Horvath Noemi, Croucher Peter I, Cakouros Dimitrios, Stewart Sheila A, Gronthos Stan, Zannettino Andrew C W, Mrozik Krzysztof M, Vandyke Kate
Myeloma Research Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.
Precision Cancer Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
Leukemia. 2025 Apr 22. doi: 10.1038/s41375-025-02621-7.
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.
意义未明的单克隆丙种球蛋白病（MGUS）进展为多发性骨髓瘤（MM）的风险随年龄增长而增加，这表明进展可能受骨髓（BM）微环境中与年龄相关的变化影响。我们推测，随着年龄增长在骨髓中积累的衰老间充质基质细胞（MSC）可能促成MGUS进展为MM。在此，我们表明，与来自老年非癌症对照的骨髓MSC一样，来自MM和MGUS患者的骨髓MSC均表现出衰老表型，其特征为形态增大、扁平，β-半乳糖苷酶活性和CDKN2A表达增加，与健康年轻个体的骨髓MSC相比增殖率降低。虽然与骨髓MSC共培养在体外会抑制MM细胞系的增殖能力，但与未衰老的MSC相比，通过辐射或在健康MSC中复制性耗竭诱导衰老可减轻这种抑制。这可能部分归因于衰老MSC中BMP拮抗剂Gremlin1表达上调，其促进MM细胞增殖。值得注意的是，MSC衰老增加的MGUS患者进展为MM的风险显著升高。总体而言，我们的数据提供了证据表明衰老MSC与年龄相关的积累可能是MGUS进展为MM的驱动因素。
