Journal Article

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

Català-Moll, Francesc, Rodríguez-Ubreva, Javier, Muntión, Sandra, Oyarzabal, Julen, Ciudad, Laura, Agirre, Xabier, Garayoa, Mercedes, Garcia-Gomez, Antonio, Esteller, Manel, de la Calle-Fabregat, Carlos, Morales, Xabier, Ballestar, Esteban, San-Segundo, Laura, Li, Tianlu, Ortiz-de-Solórzano, Carlos, Martín-Sánchez, Montserrat, Godoy-Tena, Gerard, San José-Enériz, Edurne, Prosper, Felipe

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 38/15 / 38/61 / 38/77 / 45/23 / 631/154/555 / 631/208/176/1988 / 631/67/1990/804 / 64/60 / Adult / Aged / Aged, 80 and over / Animal models / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biomedical materials / Bone diseases / Bone Diseases - diagnosis / Bone Diseases - drug therapy / Bone Diseases - genetics / Bone Diseases - pathology / Bone growth / Bone loss / Bone marrow / Bone Marrow - pathology / Deoxyribonucleic acid / Differentiation (biology) / DNA / DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA methylation / DNA Methylation - drug effects / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Epigenesis, Genetic - drug effects / Epigenetics / Female / Femur - diagnostic imaging / Femur - pathology / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Histocompatibility Antigens - metabolism / Histone-Lysine N-Methyltransferase - antagonists & inhibitors / Histone-Lysine N-Methyltransferase - metabolism / Homeobox / Humanities and Social Sciences / Humans / Inhibitors / Male / Mesenchymal stem cells / Mesenchymal Stem Cells - drug effects / Mesenchymal Stem Cells - pathology / Mesenchyme / Methyltransferase / Mice / Middle Aged / multidisciplinary / Multiple myeloma / Multiple Myeloma - complications / Multiple Myeloma - drug therapy / Multiple Myeloma - genetics / Multiple Myeloma - pathology / Osteoblastogenesis / Osteogenesis / Osteogenesis - drug effects / Osteogenesis - genetics / Science / Science (multidisciplinary) / Stromal cells / Tumors / Xenograft Model Antitumor Assays