Abstract
Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.
Highlights
Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs)
In regards to differentially methylated CpG positions (DMPs), the largest number of altered CpGs was found in MSCs from patients of the smoldering myeloma (SMM) stage compared to healthy donors (Supplementary Fig. 1A, B)
We observed the highest number of differentially variable CpG positions (DVPs) in comparison to healthy donors in MSCs isolated from monoclonal gammopathy of undetermined significance (MGUS) followed by SMM and MM patients (Supplementary Fig. 1C, D), supporting the notion that these stochastic and heterogeneous DNA methylation patterns are associated with early stages of carcinogenesis, as previously reported[24,25]
Summary
Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). The clinical stability of MGUS cases, despite displaying shared genetic lesions with MM cells, suggests that the BM microenvironment may critically modulate disease progression[6,9,10] In this regard, it has been widely shown that a complex and bidirectional relationship exists between MM cells and the BM niche, which results in oncogenesis support, anemia, immunosuppression, and uncoupling of the bone remodeling process[11]. Mesenchymal stromal cells (MSCs) are an essential cell type in the formation and function of the BM microenvironment, being the progenitors of bone-forming OBs, adipocytes, and chondroblasts, as well as the hematopoietic-supporting stroma components of the BM12.
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