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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 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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Garcia-Gomez A,Li T,de la Calle-Fabregat C,Rodríguez-Ubreva J,Ciudad L,Català-Moll F,Godoy-Tena G,Martín-Sánchez M,San-Segundo L,Muntión S,Morales X,Ortiz-de-Solórzano C,Oyarzabal J,San José-Enériz E,Esteller M,Agirre X,P

doi

10.1038/s41467-020-20715-x

subject

Has Abstract

pub_date

2021-01-18 00:00:00

pages

421

issue

1

issn

2041-1723

pii

10.1038/s41467-020-20715-x

journal_volume

12

pub_type

杂志文章

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