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Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bon...

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Autores principales: Muylaert, Catharina, Van Hemelrijck, Lien Ann, Maes, Anke, De Veirman, Kim, Menu, Eline, Vanderkerken, Karin, De Bruyne, Elke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9434119/
https://www.ncbi.nlm.nih.gov/pubmed/36059621
http://dx.doi.org/10.3389/fonc.2022.979569
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author Muylaert, Catharina
Van Hemelrijck, Lien Ann
Maes, Anke
De Veirman, Kim
Menu, Eline
Vanderkerken, Karin
De Bruyne, Elke
author_facet Muylaert, Catharina
Van Hemelrijck, Lien Ann
Maes, Anke
De Veirman, Kim
Menu, Eline
Vanderkerken, Karin
De Bruyne, Elke
author_sort Muylaert, Catharina
collection PubMed
description Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called ‘epimutations’ have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.
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spelling pubmed-94341192022-09-02 Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity? Muylaert, Catharina Van Hemelrijck, Lien Ann Maes, Anke De Veirman, Kim Menu, Eline Vanderkerken, Karin De Bruyne, Elke Front Oncol Oncology Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called ‘epimutations’ have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies. Frontiers Media S.A. 2022-08-18 /pmc/articles/PMC9434119/ /pubmed/36059621 http://dx.doi.org/10.3389/fonc.2022.979569 Text en Copyright © 2022 Muylaert, Van Hemelrijck, Maes, De Veirman, Menu, Vanderkerken and De Bruyne https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Muylaert, Catharina
Van Hemelrijck, Lien Ann
Maes, Anke
De Veirman, Kim
Menu, Eline
Vanderkerken, Karin
De Bruyne, Elke
Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?
title Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?
title_full Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?
title_fullStr Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?
title_full_unstemmed Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?
title_short Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?
title_sort aberrant dna methylation in multiple myeloma: a major obstacle or an opportunity?
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9434119/
https://www.ncbi.nlm.nih.gov/pubmed/36059621
http://dx.doi.org/10.3389/fonc.2022.979569
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