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

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 osteo...

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Autores: Gómez-García, J. A. (Juan Antonio)|||/items/960c33ab-756e-4e82-a2b1-59df73e76ce9, Li, T. (Tianlu)|||/items/9563ea30-1e54-4374-a862-fcba6bc92175, Calle, C. (Carlos) de la|||/items/8c3731c0-b848-496f-8b55-d8e06155f79f, Rodríguez-Ubreva, J. (Javier)|||/items/ebc19c3e-2fdd-4284-93d1-29e071a5ffa1, Ciudad, L. (Laura)|||/items/2a4bca5f-d5ac-41e1-9fd9-d720ee1a6eed, Català-Moll, F. (Francesc)|||/items/4d246cb6-8034-41e8-ac26-dfd77da3f14e, Godoy-Tena, G. (Gerard)|||/items/05bf37cd-34fe-4a71-ba77-9e171cb37e48, Martín-Sánchez, M. (Montserrat)|||/items/4ff2fdaf-fd8b-41f6-af19-213f027462e1, San-Segundo, L. (Laura)|||/items/5d36b724-fccf-4800-9da0-3c753a72699c, Muntion, S. (Sandra)|||/items/0f21eed5-2617-445a-b325-c69361e39a06, Morales-Urteaga, X. (Xabier)|||/items/0d40624e-57e2-4b06-a13a-90287a57b241, Ortiz-de-Solorzano, C. (Carlos)|||/items/b2c0bd13-68a7-437c-b67f-2e5f1a9f0324, Oyarzabal, J. (Julen)|||/items/5fe770fd-2181-41c9-a467-28cc89a40250, San-José-Enériz, E. (Edurne)|||/items/1c6714b1-f536-4b57-a755-83eca42e9964, Esteller, M. (Manel)|||/items/0124804c-ffb7-4533-a07c-de3aa1c30a07, Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1, Garayoa, M. (Mercedes)|||/items/a54f545f-343f-4c7d-98b6-4b7986d3ff2c, Ballestar, E. (E.)|||/items/9eba04f7-ab30-4b16-b310-5ac894ba8fe6, Aguirre-Ena, X. (Xabier)|||/items/2a000d9c-cb5c-4734-a32c-4fef79998c86
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/114913
Acceso en línea:https://hdl.handle.net/10171/114913
Access Level:acceso abierto
Palabra clave:Aberrant DNA methylation
Mesenchymal stromal cells
Multiple myeloma
Myeloma associated bone disease
Descripción
Sumario: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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