Oral Presentation 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Age-related mesenchymal stromal cell senescence is associated with progression from MGUS to multiple myeloma (#53)

Natalya Plakhova 1 2 , Krzysztof Mrozik 1 2 , Vasilios Panagopoulos 1 2 , Stan Gronthos 2 3 , Kate Vandyke 1 2 , Andrew CW Zannettino 1 2
  1. Myeloma Research Laboratory, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
  2. Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
  3. Mesenchymal Stem Cell Laboratory, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia

Senescent mesenchymal stromal cells (sMSCs) accumulate in the bone marrow (BM) with age. sMSCs display an altered secretory  phenotype, which includes the key multiple myeloma (MM) growth factor interleukin-6 (IL-6). Notably, the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM increases with advancing age and may be driven by extrinsic microenvironmental changes within the BM microenvironment. We hypothesise that age-related increases in BM-MSC senescence lead to increased proliferation of plasma cells (PC) in MGUS patients, resulting in progression to MM. 

We assessed BM-MSCs isolated from BM trephine biopsies from MGUS (n=20) and MM (n=8) patients and healthy controls (n=10). We show that BM-MSCs from MM (age: 66.5 [52-81]), and MGUS (age: 63.4 [37-84]) patients exhibit a senescent phenotype characterised by increased β-galactosidase activity, flattened cell morphology, decreased proliferation, increased gene expression of IL-6 and senescence markers such as CDKN2A when compared with healthy BM-MSCs (age: 24.6 [19-32]). The percentage of sMSCs significantly correlates with donor age in MGUS and MM patients. Notably, the risk of progression to MM is significantly elevated in MGUS patients with increased BM-MSC senescence (p=0.0294,HR; 0.18 (95% CI 0.04-0.84) and high IL-6 gene expression. Moreover, co-culture with MM and MGUS (age≥65) BM-MSCs significantly increases the proliferation of KMM1 MM cell line compared with co-culture with BM-MSCs from healthy donors or younger MGUS patients (age<65).  Induction of senescence in healthy BM-MSCs via irradiation or replicative exhaustion also increased expression of IL-6 and the proliferation of murine 5TGM1 and human KMM1 MM cell lines in co-culture assays.

Collectively, we showed for the first time that the accumulation of senescent BM-MSCs precedes progression from MGUS to MM and that BM-MSC senescence promotes MM proliferation. Moreover, elevated BM-MSC senescence at MGUS may be associated with more rapid progression to MM, which may be mediated by IL-6.