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

Antonio Garcia-Gomez (), Tianlu Li, Carlos de la Calle-Fabregat, Javier Rodríguez-Ubreva, Laura Ciudad, Francesc Català-Moll, Gerard Godoy-Tena, Montserrat Martín-Sánchez, Laura San-Segundo, Sandra Muntión, Xabier Morales, Carlos Ortiz- de-Solórzano, Julen Oyarzabal, Edurne San José-Enériz, Manel Esteller, Xabier Agirre, Felipe Prosper, Mercedes Garayoa and Esteban Ballestar ()
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Antonio Garcia-Gomez: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona
Tianlu Li: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona
Carlos de la Calle-Fabregat: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona
Javier Rodríguez-Ubreva: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona
Laura Ciudad: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona
Francesc Català-Moll: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona
Gerard Godoy-Tena: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona
Montserrat Martín-Sánchez: IBMCC (Universidad de Salamanca-CSIC) and Hospital Universitario de Salamanca-IBSAL
Laura San-Segundo: IBMCC (Universidad de Salamanca-CSIC) and Hospital Universitario de Salamanca-IBSAL
Sandra Muntión: IBMCC (Universidad de Salamanca-CSIC) and Hospital Universitario de Salamanca-IBSAL
Xabier Morales: University of Navarra, IDISNA, Ciberonc
Carlos Ortiz- de-Solórzano: University of Navarra, IDISNA, Ciberonc
Julen Oyarzabal: University of Navarra
Edurne San José-Enériz: University of Navarra, IDISNA
Manel Esteller: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Xabier Agirre: University of Navarra, IDISNA
Felipe Prosper: University of Navarra, IDISNA
Mercedes Garayoa: IBMCC (Universidad de Salamanca-CSIC) and Hospital Universitario de Salamanca-IBSAL
Esteban Ballestar: Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20715-x

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DOI: 10.1038/s41467-020-20715-x

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