Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

Abstract

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on the bone marrow (BM) microenvironment, in particular on mesenchymal stromal cells (MSCs). MSCs from MM patients exhibit an abnormal transcriptional profile, suggesting that epigenetic alterations could be governing the tumor-promoting functions of MSCs and their prolonged osteoblast (OB) suppression in MM. In this study, we analyzed the DNA methylome of BM-derived MSCs from patients with monoclonal gammopathy of undetermined significance, smoldering myeloma and symptomatic MM at diagnosis in comparison with their normal counterparts. DNA methylation alterations were found at each of the myeloma stage in association with deregulated expression levels of Homeobox genes involved in osteogenic differentiation. Moreover, these DNA methylation changes were recapitulated in vitro by exposing MSCs from healthy individuals to MM plasma cells. Pharmacological targeting of DNMTs and G9a with the dual inhibitor CM-272, reverted the expression of aberrantly methylated osteogenic regulators and promoted OB differentiation of MSCs from myeloma patients. Most importantly, in a mouse model of bone marrow-disseminated MM, administration of CM-272 prevented tumor-associated bone loss and reduced tumor burden. Our results demonstrated that not only was aberrant DNA methylation a main contributor to bone formation impairment found in MM patients, but also its targeting by CM-272 was able to reverse MM-associated bone loss.\n\nKEY POINTS- Bone marrow-derived mesenchymal stromal cells (MSCs) from monoclonal gammopathy of undetermined significance, smoldering myeloma and myeloma patients exhibit an aberrant DNA methylome compared to their healthy counterparts.\n- These DNA methylation changes are associated with an altered expression of genes of the Homeobox loci that orchestrate osteogenic differentiation of mesenchymal precursors.\n- MM plasma cell-exposed healthy MSCs recapitulate the DNA methylation alterations observed in MSCs isolated from myeloma patients.\n- Dual targeting of DNMTs and the histone methyltransferase G9a with CM-272 not only controls MM tumor burden but also prevents myeloma-associated bone loss.