The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment

• Verfasst von: Fan, Fengjuan [VerfasserIn]
• Verfasst von: Bashari, Muhammad Hasan [VerfasserIn]
• Verfasst von: Malvestiti, Stefano [VerfasserIn]
• Verfasst von: Vallet, Sonia [VerfasserIn]
• Verfasst von: Seckinger, Anja [VerfasserIn]
• Verfasst von: Hose, Dirk [VerfasserIn]
• Verfasst von: Ball, Claudia R. [VerfasserIn]
• Verfasst von: Glimm, Hanno [VerfasserIn]
• Verfasst von: Goldschmidt, Hartmut [VerfasserIn]
• Verfasst von: Jäger, Dirk [VerfasserIn]
• Verfasst von: Podar, Klaus [VerfasserIn]
• Titel: The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment
• Verf.angabe: F. Fan, M. H. Bashari, E. Morelli, G. Tonon, S. Malvestiti, S. Vallet, M. Jarahian, A. Seckinger, D. Hose, L. Bakiri, C. Sun, Y. Hu, C. R. Ball, H. Glimm, M. Sattler, H. Goldschmidt, E. F. Wagner, P. Tassone, D. Jaeger and K. Podar
• E-Jahr: 2017
• Jahr: July 2017
• Umfang: 12 S.
• Fussnoten: Advance online publication, 16 December 2016 ; Gesehen am 14.11.2018
• Titel Quelle: Enthalten in: Leukemia
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2017
• Band/Heft Quelle: 31(2017), 7, Seite 1570-1581
• ISSN Quelle: 1476-5551
• DOI: doi:10.1038/leu.2016.358
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1583705449

Abstract

Despite therapeutic advances, multiple myeloma (MM) remains an incurable disease, predominantly because of the development of drug resistance. The activator protein-1 (AP-1) transcription factor family has been implicated in a multitude of physiologic processes and tumorigenesis; however, its role in MM is largely unknown. Here we demonstrate specific and rapid induction of the AP-1 family member JunB in MM cells when co-cultured with bone marrow stromal cells. Supporting a functional key role of JunB in MM pathogenesis, knockdown of JUNB significantly inhibited in vitro MM cell proliferation and survival. Consistently, induced silencing of JUNB markedly decreased tumor growth in a murine MM model of the microenvironment. Subsequent gene expression profiling revealed a role for genes associated with apoptosis, DNA replication and metabolism in driving the JunB-mediated phenotype in MM cells. Importantly, knockdown of JUNB restored the response to dexamethasone in dexamethasone-resistant MM cells. Moreover, 4-hydroxytamoxifen-induced activation of a JunB-ER fusion protein protected dexamethasone-sensitive MM cells against dexamethasone- and bortezomib-induced cytotoxicity. In summary, our results demonstrate for the first time a specific role for AP-1/JunB in MM cell proliferation, survival and drug resistance, thereby strongly supporting that this transcription factor is a promising new therapeutic target in MM.