2. Academic Validation
  3. Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity

Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity

  • Blood Cancer J. 2024 Aug 19;14(1):138. doi: 10.1038/s41408-024-01117-4.
Judith Lind 1,  Osman Aksoy # 1,  Michaela Prchal-Murphy # 2,  Fengjuan Fan 3,  Mariateresa Fulciniti 4,  Dagmar Stoiber 5,  Latifa Bakiri 6,  Erwin F Wagner 6 7,  Elisabeth Zwickl-Traxler 8,  Martin Sattler 4,  Karoline Kollmann 2,  Sonia Vallet 1 8,  Klaus Podar 9 10
Affiliations

Affiliations

  • 1 Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
  • 2 Pharmacology and Toxicology, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria.
  • 3 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • 5 Division of Pharmacology, Department of Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
  • 6 Genes & Disease Group, Department of Laboratory Medicine, Medical University of Vienna (MUW), Vienna, Austria.
  • 7 Genes & Disease Group, Department of Dermatology, Medical University of Vienna (MUW), Vienna, Austria.
  • 8 Division of Internal Medicine 2, University Hospital Krems, Krems/ Donau, Austria.
  • 9 Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria. klaus.podar@kl.ac.at.
  • 10 Division of Internal Medicine 2, University Hospital Krems, Krems/ Donau, Austria. klaus.podar@kl.ac.at.
  • # Contributed equally.
PMID: 39160158 DOI: 10.1038/s41408-024-01117-4
Abstract

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.

Figures
Products