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

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 osteo...

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Detalhes bibliográficos
Autores: García Gómez, Antonio, Li, Tianlu, Calle Fabregat, Carlos de la, Rodríguez Ubreva, Javier, Ciudad, Laura, Català Moll, Francesc, Godoy Tena, Gerard, Martín Sánchez, Montserrat, San Segundo, Laura, Muntión, Sandra, Morales, Xabier, Ortiz de Solórzano, Carlos, Oyarzabal, Julen, San José Enériz, Edurne, Esteller, Manel, Agirre, Xabier, Prosper, Felipe, Garayoa, Mercedes, Ballestar Tarín, Esteban
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/174307
Acesso em linha:https://hdl.handle.net/2445/174307
Access Level:acceso abierto
Palavra-chave:Mieloma múltiple
ADN
Multiple myeloma
DNA
Descrição
Resumo: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. Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.

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