The Ins and Outs of Endosteal Niche Disruption in the Bone Marrow: Relevance for Myeloma Oncogenesis

SIMPLE SUMMARY: Monoclonal gammopathy cases of unknown significance occur mainly in aging people. Furthermore, it is now well-established that all cases of multiple myeloma, an aggressive lethal cancer of the bone marrow leading to bone destruction, emerge from such cases of gammopathy. In order to improve the management of myeloma, it is therefore critical to discover all of the specific factors responsible for their emergence. Here, we suggest that bone factors, i.e., bone senescence and bone inflammaging, could facilitate the emergence of these pathologies in aging people. The generalized bone loss observed in gammopathy and myeloma corresponds at the histological level to a disruption of the endosteal niche, which is both the site of hematopoiesis and the bone remodeling compartment and consists of a coupling between bone-forming osteoblasts and bone-resorbing osteoclasts. This niche undergoes a shift from an osteoblastic to an osteoclastic profile as soon as the physiological bone experiences senescence. Such a disrupted endosteal niche could represent the permissive microenvironment necessary for gammopathy and myeloma. Inside this environment, osteoclasts, through their capacity to suppress T cells but also present antigens in the bone marrow, could locally create immune changes favorable to the maintenance of gammopathy and its malignant transformation by favoring cellular instability. ABSTRACT: Multiple Myeloma (MM) and its preexisting stage, termed Monoclonal Gammopathy of Undetermined Significance (MGUS), have long been considered mainly as genomic diseases. However, the bone changes observed in both conditions have led to a reassessment of the role of the bone microenvironment, mainly the endosteal niche in their genesis. Here, we consider the disruption of the endosteal niche in the bone marrow, that is, the shift of the endosteal niche from an osteoblastic to an osteoclastic profile produced by bone senescence and inflammaging, as the key element. Thus, this disrupted endosteal niche is proposed to represent the permissive microenvironment necessary not only for the emergence of MM from MGUS but also for the emergence and maintenance of MGUS. Moreover, the excess of osteoclasts would favor the presentation of antigens (Ag) into the endosteal niche because osteoclasts are Ag-presenting cells. As such, they could significantly stimulate the presentation of some specific Ag and the clonal expansion of the stimulated cells as well as favor the expansion of such selected clones because osteoclasts are immunosuppressive. We also discuss this scenario in the Gaucher disease, in which the high incidence of MGUS and MM makes it a good model both at the bone level and the immunological level. Finally, we envisage that this endosteal niche disruption would increase the stochasticity (epigenetic and genetic instability) in the selected clones, according to our Tissue Disruption-induced cell Stochasticity (TiDiS) theory.