o:3612 Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity en 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 1552099 10.1038/s41408-024-01117-4 2024-10-17T08:40:29.653Z 44 yes 46 Judith Lind Karl Landsteiner University of Health Sciences Klaus Podar Karl Landsteiner University of Health Sciences / University Hospital Krems person 0000-0002-7414-3632 Sonia Vallet Karl Landsteiner University of Health Sciences / University Hospital Krems person Karoline Kollmann University of Veterinary Medicine Vienna person 0000-0002-7937-4245 Martin Sattler Dana-Farber Cancer Institute / Harvard Medical School person 0000-0001-5053-4199 Elisabeth Zwickl-Traxler University Hospital Krems person Erwin F. Wagner Medical University of Vienna person Latifa Bakiri Medical University of Vienna person 0000-0002-6300-2420 Dagmar Stoiber Karl Landsteiner University of Health Sciences person 0000-0002-8824-0767 Mariateresa Fulciniti Dana-Farber Cancer Institute / Harvard Medical School person 0000-0002-1432-9742 Fengjuan Fan Huazhong University of Science and Technology person 0000-0001-8727-5258 Osman Aksoy Karl Landsteiner University of Health Sciences person Michaela Prchal-Murphy University of Veterinary Medicine Vienna person application/pdf 3600413 https://phaidra.vetmeduni.ac.at/o:3612 no yes 16 70 1552253 Blood Cancer Journal 12 14 1 Springer 2024