phaidra.vetmeduni.ac.at o:3612 DOI 10.1038/s41408-024-01117-4 Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity Deregulation of transcription factors (TFs) leading to uncontrolled proliferation of tumor cells within the microenvironment represents a hallmark of cancer. 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 via targeting the master regulator BRD4 by either siRNA-mediated knockdown or treatment with the novel proteolysis targeting chimera (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. eng Multiple Myeloma Genetics Drug Therapy Pathology Metabolism; Humans; Animals; Mice; Proto-Oncogene Proteins C-myc Genetics Metabolism; Transcription Factors Genetics Metabolism; Gene Expression Regulation, Neoplastic Drug effects; Cell Line, Tumor; Xenograft Model Antitumor Assays; Proto-Oncogene Proteins C-jun Metabolism Genetics 2024-10-18T09:12:58.714Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Lind;Judith; FN:Judith Lind END:VCARD BEGIN:VCARD VERSION:3.0 N:Podar;Klaus; FN:Klaus Podar X-ORCID:https://orcid.org/0000-0002-7414-3632 END:VCARD BEGIN:VCARD VERSION:3.0 N:Vallet;Sonia; FN:Sonia Vallet END:VCARD BEGIN:VCARD VERSION:3.0 N:Kollmann;Karoline; FN:Karoline Kollmann X-ORCID:https://orcid.org/0000-0002-7937-4245 END:VCARD BEGIN:VCARD VERSION:3.0 N:Sattler;Martin; FN:Martin Sattler X-ORCID:https://orcid.org/0000-0001-5053-4199 END:VCARD BEGIN:VCARD VERSION:3.0 N:Zwickl-Traxler;Elisabeth; FN:Elisabeth Zwickl-Traxler END:VCARD BEGIN:VCARD VERSION:3.0 N:Wagner;Erwin F.; FN:Erwin F. Wagner END:VCARD BEGIN:VCARD VERSION:3.0 N:Bakiri;Latifa; FN:Latifa Bakiri X-ORCID:https://orcid.org/0000-0002-6300-2420 END:VCARD BEGIN:VCARD VERSION:3.0 N:Stoiber;Dagmar; FN:Dagmar Stoiber X-ORCID:https://orcid.org/0000-0002-8824-0767 END:VCARD BEGIN:VCARD VERSION:3.0 N:Fulciniti;Mariateresa; FN:Mariateresa Fulciniti X-ORCID:https://orcid.org/0000-0002-1432-9742 END:VCARD BEGIN:VCARD VERSION:3.0 N:Fan;Fengjuan; FN:Fengjuan Fan X-ORCID:https://orcid.org/0000-0001-8727-5258 END:VCARD BEGIN:VCARD VERSION:3.0 N:Aksoy;Osman; FN:Osman Aksoy END:VCARD BEGIN:VCARD VERSION:3.0 N:Prchal-Murphy;Michaela; FN:Michaela Prchal-Murphy END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 3600413 https://phaidra.vetmeduni.ac.at/o:3612 https://phaidra.vetmeduni.ac.at/api/object/o:3612/thumbnail LOMv1.0 discipline