{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:01:00Z","timestamp":1790272860833,"version":"4.1.0"},"reference-count":119,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012541","name":"Hercules Foundation","doi-asserted-by":"publisher","award":["AUHA\/13\/012"],"award-info":[{"award-number":["AUHA\/13\/012"]}],"id":[{"id":"10.13039\/501100012541","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Foundation against cancer (Belgium)","award":["7872"],"award-info":[{"award-number":["7872"]}]},{"name":"Research Foundation Flanders (FWO)","award":["G1179120N"],"award-info":[{"award-number":["G1179120N"]}]},{"name":"Research Foundation Flanders (FWO)","award":["G059713N"],"award-info":[{"award-number":["G059713N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies for multiple myeloma and other malignancies. Both ferroptosis and the epigenetic machinery are heavily influenced by oxidative stress and iron metabolism changes. Yet, only a limited number of epigenetic enzymes and modifications have been identified as ferroptosis regulators. In this study, we found that MM1 multiple myeloma cells are sensitive to ferroptosis induction and epigenetic reprogramming by RSL3, irrespective of their glucocorticoid-sensitivity status. LC-MS\/MS analysis revealed the formation of non-heme iron-histone complexes and altered expression of histone modifications associated with DNA repair and cellular senescence. In line with this observation, EPIC BeadChip measurements of significant DNA methylation changes in ferroptotic myeloma cells demonstrated an enrichment of CpG probes located in genes associated with cell cycle progression and senescence, such as Nuclear Receptor Subfamily 4 Group A member 2 (NR4A2). Overall, our data show that ferroptotic cell death is associated with an epigenomic stress response that might advance the therapeutic applicability of ferroptotic compounds.<\/jats:p>","DOI":"10.3390\/ijms222212234","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T08:10:22Z","timestamp":1636704622000},"page":"12234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1053-2409","authenticated-orcid":false,"given":"Emilie","family":"Logie","sequence":"first","affiliation":[{"name":"Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7368-1762","authenticated-orcid":false,"given":"Bart","family":"Van Puyvelde","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-1470","authenticated-orcid":false,"given":"Bart","family":"Cuypers","sequence":"additional","affiliation":[{"name":"Biomedical Informatics Network Antwerp (Biomina), Department of Computer Science, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Schepers","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herald","family":"Berghmans","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4105-5126","authenticated-orcid":false,"given":"Jelle","family":"Verdonck","sequence":"additional","affiliation":[{"name":"Center for Environment and Health, Department of Public Health and Primary Care, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8217-2564","authenticated-orcid":false,"given":"Kris","family":"Laukens","sequence":"additional","affiliation":[{"name":"Biomedical Informatics Network Antwerp (Biomina), Department of Computer Science, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4764-8835","authenticated-orcid":false,"given":"Lode","family":"Godderis","sequence":"additional","affiliation":[{"name":"Center for Environment and Health, Department of Public Health and Primary Care, KU Leuven, 3000 Leuven, Belgium"},{"name":"IDEWE, External Service for Prevention and Protection at Work, 3001 Heverlee, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-3509","authenticated-orcid":false,"given":"Maarten","family":"Dhaenens","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0635-661X","authenticated-orcid":false,"given":"Dieter","family":"Deforce","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0161-7355","authenticated-orcid":false,"given":"Wim","family":"Vanden Berghe","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1053\/j.seminoncol.2016.11.004","article-title":"Multiple myeloma epidemiology and survival: A unique malignancy","volume":"43","author":"Kazandjian","year":"2016","journal-title":"Semin. 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