Abstract Multiple myeloma (MM) is an incurable, plasma cell (PC) malignancy that progresses from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Although MGUS and SMM PCs exhibit similar oncogenic mutations to MM PCs, they are considered benign and it is unclear what drives tumorigenesis of these pre-malignant PCs. Aging is the primary risk factor for cancers, including MM; it is therefore unsurprising that aging and tumorigenesis exhibit shared mechanisms. One of these shared mechanisms is cellular senescence. Cellular senescence is induced in response to cellular stress, such as oncogenic mutations, and activates growth arrest to prevent tumor formation. However, the accumulation of senescent cells with age contributes to aging pathologies, including cancer. Although deletion or inhibition of genes necessary for senescence induction leads to tumor formation, elimination of senescent cells reduces tumor incidence in aged mice. This suggests that senescent cell accumulation may create a pro- tumorigenic microenvironment; alternatively, pre-tumor cells may themselves be senescent and targeted by senescent cell elimination strategies. In support of this, we found that both MGUS and SMM PCs have enrichment of cellular senescence genes. In addition, SMM PCs show characteristics of late-senescence, including an interferon senescence-associated secretory phenotype (SASP) and the accumulation of cytosolic ssDNA and DNA:RNA hybrids that are associated with increased genomic instability. These findings support a role for PC senescence in monoclonal gammopathies, and suggest a potential mechanism that may ultimately drive tumorigenesis. Importantly, clonal PCs have also been shown to induce senescence in the bone marrow microenvironment (BMME), suggesting additional mechanisms by which senescence may promote a permissive niche for MM tumorigenesis. Thus, we hypothesize that senescence within PCs and their proximate BMME drives progression of MGUS/SMM to MM. In this application, we propose to use genetic mouse models and human patient-derived cells and bone biopsies to ascertain the mechanisms by which senescence drives tumorigenesis through both direct effects on pre-tumor cells and on the BMME. The results of these studies will define a role for senescence, a common aging mechanism, in tumorigenesis. We anticipate that these findings can be rapidly translated to clinical trials targeting the progression of monoclonal gammopathies to MM.

Project Narrative Multiple myeloma (MM) is an incurable hematopoietic malignancy that progresses from benign monoclonal gammopathy precursor conditions. Oncogenic mutations in MM are similar to those found in the precursor conditions, and it is not clear what ultimately drives tumorigenesis. Understanding these mechanisms may lead to the development of therapeutic strategies to prevent cancer development in these patients.