The Role of Bone Marrow Mesenchymal Stromal Cell Senescence in Multiple Myeloma
Date
2022
Authors
Plakhova, Natalya
Editors
Advisors
Zannettino, Andrew
Vandyke, Kate
Mrazik, Krzysztof
Vandyke, Kate
Mrazik, Krzysztof
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Abstract
Multiple myeloma (MM) is a malignancy characterised by the uncontrolled clonal proliferation of
neoplastic plasma cells (PCs) within the bone marrow (BM). MM PCs rely on mesenchymal stromal cells
(MSCs) within the BM for their proliferation and survival. MM is universally preceded by an
asymptomatic precancerous condition, monoclonal gammopathy of undetermined significance
(MGUS). The risk of progression of MGUS-to-MM increases with advancing age, concurrent to the
accumulation of senescent BM-MSCs. Moreover, MSC senescence has been implicated in promoting cancer
growth, suggesting that it could play a role in MM progression.
Here, we characterised BM-MSC senescence in ex vivo expanded BM-MSCs isolated from BM trephine
biopsies from MGUS (median age: 67.5 [range: 42-84]) and MM (age: 70 [52- 84]) patients and aged
(age: 88 [68-94]) and young (age: 21 [17-26]) healthy subjects by evaluating B-galactosidase
activity, proliferation and cellular morphology. These studies confirmed that age-related increases
in BM-MSC senescence are a characteristic feature of MGUS and MM. Additionally, there was no
significant difference in the number of senescent BM-MSCs between aged healthy subjects, MGUS and
MM patients, suggesting that this was not a function of disease stage. Strikingly, we found that
the risk of progression to MM is significantly elevated in MGUS patients with increased BM-MSC
senescence. Furthermore, we demonstrated that the induction of BM-MSC senescence promoted the
proliferation of MM PCs relative to co-culture with non-senescent controls.
Senescent MSCs display a senescence associated secretory phenotype (SASP) characterised
by increased production of growth molecules. Notably, we identified that BM-MSC gene expression of the well-established SASP factor interleukin-6 (lL-6) and novel SASP factor Gremlin1
(GREMJ) at MGUS was predictive of progression to MM in our cohort. However, our studies showed that
the MM growth-promoting effects of irradiated senescent BM-MSCs were not mediated by IL-6 and or
Gremlin1 in vitro. Further RNA sequencing analysis of irradiated murine stroma identified 17
putative SASP factors, which were upregulated with irradiation and are expressed by MM patient
BM-MSCs. These include, CXCL-12, GAS6 and IGF-1, which have been previously implicated in promoting
MM PC growth.
To investigate whether BM-MSC senescence plays a role in MM PC proliferation in vivo, we utilised a
mouse model where cre-mediated knockout of enhancer of zeste 2 (EZH2) is driven by the mesenchymal
Prrx1 promoter, which has previously been reported to induce senescence of mesenchymal lineage
cells in vivo. Unexpectedly, our studies revealed that senescent cell burden within the bones and
of BM-MSCs of EZH2⁺/⁻ mice was significantly reduced relative to that of WT controls. Furthermore,
we did not detect a difference in Vk*Myc MM tumour growth within the BM following intravenous
injection in these animals.
Collectively, our findings suggest that the accumulation of senescent BM-MSCs with advancing
biological age could constitute a growth-permissive niche at MGUS and facilitate the progression to
MM. Excitingly, this highlights the potential utility of these cells as a novel therapeutic target
and provides the impetus for future studies investigating the utility of senolytics and agents that
inhibit the pro-tumorigenic effects of SASP to prevent MGUS-to-
MM progression.
School/Discipline
School of Biomedicine
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 2023
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