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Title: Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease
Author: 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
Keywords: Mieloma múltiple
Multiple myeloma
Issue Date: 18-Jan-2021
Publisher: Springer Nature
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. 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.
Note: Reproducció del document publicat a:
It is part of: Nature Communications, 2021, vol. 12
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Ciències Fisiològiques)

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