Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease.
Antonio Garcia-GomezTianlu LiCarlos de la Calle-FabregatJavier Rodríguez-UbrevaLaura CiudadFrancesc Català-MollGerard Godoy-TenaMontserrat Martín-SánchezLaura San-SegundoSandra MuntiónXabier MoralesCarlos Ortiz de SolórzanoJulen OyarzabalEdurne San José-EnérizManel EstellerXabier AgirreFelipe ProsperMercedes GarayoaEsteban BallestarPublished in: Nature communications (2021)
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.
Keyphrases
- mesenchymal stem cells
- bone marrow
- dna methylation
- multiple myeloma
- umbilical cord
- bone loss
- gene expression
- genome wide
- cancer therapy
- poor prognosis
- newly diagnosed
- bone mineral density
- bone regeneration
- induced apoptosis
- binding protein
- cell proliferation
- soft tissue
- transcription factor
- mouse model
- drug delivery
- long non coding rna
- cell cycle arrest