Titel (eng)

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

Autor*in

Judith Lind   Karl Landsteiner University of Health Sciences

Klaus Podar   Karl Landsteiner University of Health Sciences / University Hospital Krems

Sonia Vallet   Karl Landsteiner University of Health Sciences / University Hospital Krems

Karoline Kollmann   University of Veterinary Medicine Vienna

Martin Sattler   Dana-Farber Cancer Institute / Harvard Medical School

Elisabeth Zwickl-Traxler   University Hospital Krems

Erwin F. Wagner   Medical University of Vienna

Latifa Bakiri   Medical University of Vienna

Dagmar Stoiber   Karl Landsteiner University of Health Sciences

Mariateresa Fulciniti   Dana-Farber Cancer Institute / Harvard Medical School

Fengjuan Fan   Huazhong University of Science and Technology

Osman Aksoy   Karl Landsteiner University of Health Sciences

Michaela Prchal-Murphy   University of Veterinary Medicine Vienna

Verlag

Springer

Beschreibung (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.

Sprache des Objekts

Englisch

Datum

2024

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

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

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