The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse
Abstract Background The plasma cell malignancy multiple myeloma (MM) remains incurable due to the inevitable development of drug resistance (DR). Epigenetic modifiers are frequently mutated or deregulated in MM patients, contributing to MM progression and relapse. Overexpression of the de novo DNA m...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-025-03382-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849699730774294528 |
|---|---|
| author | Catharina Muylaert Lien Ann Van Hemelrijck Arne Van der Vreken Robbe Heestermans Hatice Satilmis Emma Verheye Elina Alaterre Catharina Olsen Nathan De Beule Kim De Veirman Eline Menu Karin Vanderkerken Jérôme Moreaux Elke De Bruyne |
| author_facet | Catharina Muylaert Lien Ann Van Hemelrijck Arne Van der Vreken Robbe Heestermans Hatice Satilmis Emma Verheye Elina Alaterre Catharina Olsen Nathan De Beule Kim De Veirman Eline Menu Karin Vanderkerken Jérôme Moreaux Elke De Bruyne |
| author_sort | Catharina Muylaert |
| collection | DOAJ |
| description | Abstract Background The plasma cell malignancy multiple myeloma (MM) remains incurable due to the inevitable development of drug resistance (DR). Epigenetic modifiers are frequently mutated or deregulated in MM patients, contributing to MM progression and relapse. Overexpression of the de novo DNA methyltransferase 3B (DNMT3B) in MM has been reported, correlating with poor prognosis. However, its exact role in MM cell biology and relapse remains elusive. Methods To evaluate the basal expression and prognostic value of DNMT3B mRNA in terms of overall survival the publicly available gene expression profiling datasets GSE2658, GSE9782, GSE4581, E-MTAB-372, E-TABM-1088 and E-TABM-937 were used. Both the DNMT3B selective inhibitor Nanaomycin A and genetic knockdown using a doxycycline inducible shRNA against DNMT3B were used to target DNMT3B. Viability and apoptosis were assessed using respectively a CellTiter-Glo assay and AnnexinV/7AAD stainings. Cell proliferation was measured by BrdU incorporation and cell cycle analysis, while the clonogenic capacity was evaluated by a colony formation assay. Finally, RNA-seq was performed upon genetic knockdown. Results Here, we show that DNMT3B is significantly increased in the relapsed setting and high DNMT3B levels are strongly correlating with disease progression and high-risk disease, irrespective of the treatment. Targeting DNMT3B using either genetic inhibition or the selective inhibitor Nanaomycin A strongly impaired MM cell growth, survival and clonogenicity. Moreover, Nanaomycin A reduced viability of primary MM cells from newly diagnosed and relapsed patients. Mechanistic studies revealed that DNMT3B inhibition mainly affects cell cycle and stemness-related transcriptional programs. Notably, DNMT3B depletion affected the stability of the master cell cycle regulator MYC, thereby reducing c-MYC levels and cell viability both in parental and c-MYC overexpressing cells. Finally, Nanaomycin A (re)sensitized MM cells to bortezomib, melphalan and anti-CD38 monoclonal antibodies (daratumumab, isatuximab). Conclusion Collectively, our findings uncover DNMT3B as a targetable vulnerability in high-risk patients with high DNMT3B/MYC levels. |
| format | Article |
| id | doaj-art-3d449a4cfce245aba67e77075d2c9d63 |
| institution | DOAJ |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-3d449a4cfce245aba67e77075d2c9d632025-08-20T03:18:31ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-04-0144111810.1186/s13046-025-03382-yThe de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapseCatharina Muylaert0Lien Ann Van Hemelrijck1Arne Van der Vreken2Robbe Heestermans3Hatice Satilmis4Emma Verheye5Elina Alaterre6Catharina Olsen7Nathan De Beule8Kim De Veirman9Eline Menu10Karin Vanderkerken11Jérôme Moreaux12Elke De Bruyne13Translational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel (UZ Brussel)Translational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselDiag2TecClinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel)Translational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselIGH, CNRS, University of MontpellierTranslational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit BrusselAbstract Background The plasma cell malignancy multiple myeloma (MM) remains incurable due to the inevitable development of drug resistance (DR). Epigenetic modifiers are frequently mutated or deregulated in MM patients, contributing to MM progression and relapse. Overexpression of the de novo DNA methyltransferase 3B (DNMT3B) in MM has been reported, correlating with poor prognosis. However, its exact role in MM cell biology and relapse remains elusive. Methods To evaluate the basal expression and prognostic value of DNMT3B mRNA in terms of overall survival the publicly available gene expression profiling datasets GSE2658, GSE9782, GSE4581, E-MTAB-372, E-TABM-1088 and E-TABM-937 were used. Both the DNMT3B selective inhibitor Nanaomycin A and genetic knockdown using a doxycycline inducible shRNA against DNMT3B were used to target DNMT3B. Viability and apoptosis were assessed using respectively a CellTiter-Glo assay and AnnexinV/7AAD stainings. Cell proliferation was measured by BrdU incorporation and cell cycle analysis, while the clonogenic capacity was evaluated by a colony formation assay. Finally, RNA-seq was performed upon genetic knockdown. Results Here, we show that DNMT3B is significantly increased in the relapsed setting and high DNMT3B levels are strongly correlating with disease progression and high-risk disease, irrespective of the treatment. Targeting DNMT3B using either genetic inhibition or the selective inhibitor Nanaomycin A strongly impaired MM cell growth, survival and clonogenicity. Moreover, Nanaomycin A reduced viability of primary MM cells from newly diagnosed and relapsed patients. Mechanistic studies revealed that DNMT3B inhibition mainly affects cell cycle and stemness-related transcriptional programs. Notably, DNMT3B depletion affected the stability of the master cell cycle regulator MYC, thereby reducing c-MYC levels and cell viability both in parental and c-MYC overexpressing cells. Finally, Nanaomycin A (re)sensitized MM cells to bortezomib, melphalan and anti-CD38 monoclonal antibodies (daratumumab, isatuximab). Conclusion Collectively, our findings uncover DNMT3B as a targetable vulnerability in high-risk patients with high DNMT3B/MYC levels.https://doi.org/10.1186/s13046-025-03382-yMultiple myelomaEpigeneticsDNMT3BRelapse |
| spellingShingle | Catharina Muylaert Lien Ann Van Hemelrijck Arne Van der Vreken Robbe Heestermans Hatice Satilmis Emma Verheye Elina Alaterre Catharina Olsen Nathan De Beule Kim De Veirman Eline Menu Karin Vanderkerken Jérôme Moreaux Elke De Bruyne The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse Journal of Experimental & Clinical Cancer Research Multiple myeloma Epigenetics DNMT3B Relapse |
| title | The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse |
| title_full | The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse |
| title_fullStr | The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse |
| title_full_unstemmed | The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse |
| title_short | The de novo DNA methyltransferase 3B is a novel epigenetic regulator of MYC in multiple myeloma, representing a promising therapeutic target to counter relapse |
| title_sort | de novo dna methyltransferase 3b is a novel epigenetic regulator of myc in multiple myeloma representing a promising therapeutic target to counter relapse |
| topic | Multiple myeloma Epigenetics DNMT3B Relapse |
| url | https://doi.org/10.1186/s13046-025-03382-y |
| work_keys_str_mv | AT catharinamuylaert thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT lienannvanhemelrijck thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT arnevandervreken thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT robbeheestermans thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT haticesatilmis thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT emmaverheye thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT elinaalaterre thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT catharinaolsen thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT nathandebeule thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT kimdeveirman thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT elinemenu thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT karinvanderkerken thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT jeromemoreaux thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT elkedebruyne thedenovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT catharinamuylaert denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT lienannvanhemelrijck denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT arnevandervreken denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT robbeheestermans denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT haticesatilmis denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT emmaverheye denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT elinaalaterre denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT catharinaolsen denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT nathandebeule denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT kimdeveirman denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT elinemenu denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT karinvanderkerken denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT jeromemoreaux denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse AT elkedebruyne denovodnamethyltransferase3bisanovelepigeneticregulatorofmycinmultiplemyelomarepresentingapromisingtherapeutictargettocounterrelapse |