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However, the biological and clinical impact of transcriptional interference, particularly in multiple myeloma (MM) cells, remains poorly understood. The present study shows for the first time that MYC and JUNB, two crucial TFs implicated in MM pathogenesis, orchestrate distinct transcriptional programs. Specifically, our data revealed that expression levels of MYC, JUNB, and their respective downstream targets do not correlate and that their global chromatin-binding patterns are not significantly overlapping. Mechanistically, MYC expression was not affected by JUNB knockdown, and conversely, JUNB expression and transcriptional activity were not affected by MYC knockdown. Moreover, suppression of MYC levels in MM cells <jats:italic>via<\/jats:italic> targeting the master regulator BRD4 by either siRNA-mediated knockdown or treatment with the novel <jats:italic>proteolysis targeting chimera<\/jats:italic> (PROTAC) MZ-1 overcame bone marrow (BM) stroma cell\/IL-6-induced MYC- but not MEK-dependent JUNB-upregulation and transcriptional activity. Consequently, targeting of the two non-overlapping MYC- and JUNB-transcriptoms by MZ-1 in combination with genetic or pharmacological JUNB-targeting approaches synergistically enhanced MM cell death, both in 2D and our novel dynamic 3D models of the BM milieu as well as in murine xenografts. In summary, our data emphasize the opportunity to employ MYC and JUNB dual-targeting treatment strategies in MM as another exciting approach to further improve patient outcomes.<\/jats:p>","DOI":"10.1038\/s41408-024-01117-4","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T11:03:14Z","timestamp":1724065394000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity"],"prefix":"10.1038","volume":"14","author":[{"given":"Judith","family":"Lind","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osman","family":"Aksoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Prchal-Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8727-5258","authenticated-orcid":false,"given":"Fengjuan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1432-9742","authenticated-orcid":false,"given":"Mariateresa","family":"Fulciniti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8824-0767","authenticated-orcid":false,"given":"Dagmar","family":"Stoiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6300-2420","authenticated-orcid":false,"given":"Latifa","family":"Bakiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin F.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Zwickl-Traxler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5053-4199","authenticated-orcid":false,"given":"Martin","family":"Sattler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline","family":"Kollmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Vallet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7414-3632","authenticated-orcid":false,"given":"Klaus","family":"Podar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"1117_CR1","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.6004\/jnccn.2023.0061","volume":"21","author":"SK Kumar","year":"2023","unstructured":"Kumar SK, Callander NS, Adekola K, Anderson LD Jr, Baljevic M, Baz R, et al. 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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Primary tumor cells and BMSCs were isolated from BM aspirates after informed consent was obtained in accordance with the Declaration of Helsinki. The collection and use of primary cells have been approved by the Ethics Committee of Lower Austria (approval number GS1-EK-4\/407-2019). Isolation, purification, and culture of BMSCs and primary MM cells were performed, as previously described []. All experimental animal procedures and protocols have been approved by the Ethics and Animal Welfare Committee of the University of Veterinary Medicine (vetmeduni), Vienna, in accordance with the University\u00b4s guidelines for Good Scientific Practice and authorized by the Austrian Federal Ministry of Education, Science and Research (BMBWF GZ 68.205\/0174-V\/3b\/2018, BMWFW-68.205\/0093-WF\/V\/3b\/2015, and 2022-0.404.452) institutional ethical committee at the vetmeduni, Vienna.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"138"}}