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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.979569/full |
| _version_ | 1811214659604185088 |
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| author | Catharina Muylaert Lien Ann Van Hemelrijck Anke Maes Kim De Veirman Eline Menu Karin Vanderkerken Elke De Bruyne |
| author_facet | Catharina Muylaert Lien Ann Van Hemelrijck Anke Maes Kim De Veirman Eline Menu Karin Vanderkerken Elke De Bruyne |
| author_sort | Catharina Muylaert |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T06:08:35Z |
| format | Article |
| id | doaj.art-aa9ed1f467844905aa29fbd891cea6e2 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T06:08:35Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-aa9ed1f467844905aa29fbd891cea6e22022-12-22T03:44:47ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-08-011210.3389/fonc.2022.979569979569Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?Catharina MuylaertLien Ann Van HemelrijckAnke MaesKim De VeirmanEline MenuKarin VanderkerkenElke De BruyneDrug 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.https://www.frontiersin.org/articles/10.3389/fonc.2022.979569/fullmultiple myelomaepigeneticsDNA methylation modifiersMM cell plasticityDNMTi |
| spellingShingle | Catharina Muylaert Lien Ann Van Hemelrijck Anke Maes Kim De Veirman Eline Menu Karin Vanderkerken Elke De Bruyne Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity? Frontiers in Oncology multiple myeloma epigenetics DNA methylation modifiers MM cell plasticity DNMTi |
| 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 | multiple myeloma epigenetics DNA methylation modifiers MM cell plasticity DNMTi |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.979569/full |
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