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Cited by 57Multiple Myeloma Research and TreatmentsEpigenetics and DNA MethylationBone Tumor Diagnosis and Treatments

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

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Garcia-Gomez, Antonio, Li, Tianlu, de la Calle-Fabregat, Carlos, Rodríguez-Ubreva, Javier, Ciudad, Laura, Català-Moll, Francesc, Godoy-Tena, Gerard, Martín-Sánchez, Montserrat +11 more·2021·Nature Communications
DOI 10.1038/s41467-020-20715-xPMC PMC7813865

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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.

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  • In a study by Garcia Gomez and colleagues, CM-272 treatment prevented tumor-associated bone loss and reduced tumor burden in the murine myeloma model.

    “In this regard, in a study by Garcia Gomez and colleagues on pharmacological targeting of DNMTs and G9a with the dual inhibitor CM-272, they showed that CM-272 treatment prevented tumor-associated bone loss and reduced tumor burden in the murine myeloma model.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [138]

  • DNA methylation changes in BM-MSCs from MM are especially seen in Homeobox genes that play a role in osteogenic differentiation.

    “These changes were especially seen in Homeobox genes that play a role in osteogenic differentiation and are linked to these changes in DNA methylation can also be seen in the lab when MSCs from healthy people are exposed to MM cells [138].”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [138]

  • Epigenetic abnormalities in patients with MM lead to bone formation disorders and targeting it by CM-272 can reverse the process of myeloma-associated bone disease.

    “They concluded that epigenetic abnormalities in patients with MM lead to bone formation disorders and targeting it by CM-272 can reverse the process of Myeloma associated bone disease [138].”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [138]

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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., Prosper, F., Garayoa, M., & Ballestar, E.
Affiliations
  • Institut d'Investigació Biomédica de Bellvitge (ES)
  • Universidad de Salamanca (ES)
  • Centro de Investigación Médica Aplicada (ES)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
  • Navarre Institute of Health Research (ES)
Corresponding author
Ballestar, Esteban
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-01-18
Volume
12
Issue
1
Pages
421-421
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-20715-x
PMC
PMC7813865
OpenAlex
W3122583638
Cited by
57
References
79
Citations by year
2026: 8 · 2025: 11 · 2024: 5 · 2023: 10 · 2022: 15 · 2021: 7 · 2020: 1
FWCI
6.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Multiple Myeloma Research Foundation
  • Fundación Ramón Areces (PI19/01384)
  • Fundació la Marató de TV3
  • Ministerio de Ciencia, Innovación y Universidades (PI19/01384, RTI2018‐094494‐B‐C22, RTI2018)
  • Centres de Recerca de Catalunya
  • Cancer Research UK (PI17/00701, PI19/01352)
  • Generalitat de Catalunya
  • Ministerio de Economía y Competitividad (SAF2014-55942-R)
  • Ministerio de Ciencia e Innovación (SAF2017‐88086‐R, RTI2018, PI15/)
  • Associazione Italiana per la Ricerca sul Cancro
  • Instituto de Salud Carlos III (PI19/01384, PI15/02156, PI19/01352, Marató de TV3, SAF2014-55942-R, PI17/00701, CB16/12/00489)
  • European Regional Development Fund (RTI2018-094494-B-C22, CB16/12/00489, SAF2017, RTI2018)
  • Agencia Estatal de Investigación (RTI2018‐094494‐B‐C22)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
Keywords
multiple myeloma, mesenchymal stem cells, DNA methylation, epigenetic regulation, homeobox genes, osteogenic differentiation, DNMT inhibitors, G9a, bone marrow microenvironment
MeSH terms
Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Bone Diseases, Bone Marrow, DNA (Cytosine-5-)-Methyltransferases, Enzyme Inhibitors, Female, Femur, Histocompatibility Antigens, Humans, Male, Middle Aged, Multiple Myeloma, Osteogenesis, Histone-Lysine N-Methyltransferase, Gene Expression Regulation, Neoplastic, DNA Methylation, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Mice, Mesenchymal Stem Cells

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