https://phaidra.vetmeduni.ac.at/o:3612 Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity Lind, Judith Judith Lind Karl Landsteiner University of Health Sciences Podar, Klaus Klaus Podar 0000-0002-7414-3632 Karl Landsteiner University of Health Sciences / University Hospital Krems Vallet, Sonia Sonia Vallet Karl Landsteiner University of Health Sciences / University Hospital Krems Kollmann, Karoline Karoline Kollmann 0000-0002-7937-4245 University of Veterinary Medicine Vienna Sattler, Martin Martin Sattler 0000-0001-5053-4199 Dana-Farber Cancer Institute / Harvard Medical School Zwickl-Traxler, Elisabeth Elisabeth Zwickl-Traxler University Hospital Krems Wagner, Erwin F. Erwin F. Wagner Medical University of Vienna Bakiri, Latifa Latifa Bakiri 0000-0002-6300-2420 Medical University of Vienna Stoiber, Dagmar Dagmar Stoiber 0000-0002-8824-0767 Karl Landsteiner University of Health Sciences Fulciniti, Mariateresa Mariateresa Fulciniti 0000-0002-1432-9742 Dana-Farber Cancer Institute / Harvard Medical School Fan, Fengjuan Fengjuan Fan 0000-0001-8727-5258 Huazhong University of Science and Technology Aksoy, Osman Osman Aksoy Karl Landsteiner University of Health Sciences Prchal-Murphy, Michaela Michaela Prchal-Murphy University of Veterinary Medicine Vienna Springer text eng 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. 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 http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3612/download 10.1038/s41408-024-01117-4 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Blood Cancer Journal 14(1) (2024) Blood Cancer Journal 14 1 3.43 MB 2024