Postdoctoral Research Fellow Mayo Clinic Rochester, Minnesota, United States
Introduction: Multiple Myeloma (MM) progresses from monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM). Despite similar primary genetic events as MM, MGUS and SMM are non- or low-proliferative; however, stable MGUS patients are at increased risk for osteoporotic fracture and show reduced overall survival due to aging co-morbidities. Since oncogenes and DNA damage drive senescent growth arrest, we hypothesize that stable MGUS and SMM pre-malignant PCs exhibit senescence features.
Methods: We performed gene set enrichment analysis (GSEA) of a published human PC gene array dataset (GSE5900). Immunostaining and fluorescent in situ hybridization were performed to evaluate senescence in MGUS, SMM and MM patient PCs and trephine bone biopsies from MGUS and SMM patients that progressed or not to MM. Lastly, quantitative PCR was used to validate senescence gene expression changes in MGUS, SMM, and MM PCs.
Results: MGUS and SMM PCs exhibited significant enrichment for senescence phenotyping gene sets that were distinct from aging. PCs from bone marrow aspirates were identified as senescent based on the Loss of LMNB1 (LoL, < 50%) and senescence associated distension of satellites (SADS, ≥3/cell). PCs from patients with stable MGUS (N=4) exhibited increased percentage of senescent PCs compared to SMM and MM, while stable vs progressing SMM PCs (stable vs progressed ≤5 years, n=6-8) were unchanged. However, PCs from stable, but not progressing SMM, had increased expression of senescence genes (CDKN2A, TP53, BCL2, and IL1B). Both stable MGUS and SMM PCs showed a significant increase in the expression of the retrotransposable element, L1HS, which is increased with senescence, compared to PCs from SMM progressors. Trephine biopsy cells were scored as senescent based on LoL and loss of nuclear HMGB1. Stable MGUS patients exhibited increased percentage of senescent PCs compared to MM and MGUS patients that progressed ≤10 years (n=20-40). Senescent PCs in trephine biopsies correlated with senescence in the bone marrow microenvironment (BMME). Of interest, MGUS and SMM PCs from patients that progressed ≤10 years both exhibited a significant loss in neighboring senescent BMME compared to stable MGUS and SMM PCs.
Conclusions: Overall, we demonstrate the presence of stage-specific senescence features in PCs from stable MGUS and SMM patients; these features are decreased in PCs from SMM progressors and MM, consistent with the protective effect of senescence against tumorigenesis. Thus, evaluating PC senescence in MGUS and SMM may have prognostic value to identify patients that will progress to MM. Importantly, given the increased risk for osteoporotic fracture and reduced overall survival in stable MGUS patients, the senescence-related protection against MM may come at the expense of premature aging. Ongoing studies are evaluating the safety and therapeutic utility of ablating pre-malignant senescent cells in MGUS and SMM.
