Journal
LEUKEMIA
Volume 31, Issue 7, Pages 1570-1581Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.358
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Funding
- B Braun Stiftungs
- DAAD-Indonesian German Scholarship Programme for doctoral fellowship
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [9965]
- Deutsche Forschungsgemeinschaft (Bonn, Germany) [SFB/TRR79]
- EU
- German Research Council (DFG) [KFO 227]
- Baden-Wurttemberg Stiftung
- DFG Collaborative Research Center 873
- Dietmar Hopp Stiftung
- German Ministry of Education and Science
- DFG
- Banco Bilbao Vizcaya Argentaria (BBVA) Foundation
- European Research Council [ERC FCK/2008/37]
- Italian Association for Cancer Research (AIRC) [9980]
- Heidelberg University Association
- DKFZ -HIPO [H034]
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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.
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