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Leukemia. 2017 Jul;31(7):1570-1581. doi: 10.1038/leu.2016.358. Epub 2016 Nov 28.

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

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Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
University 'Magna Græcia' of Catanzaro, Catanzaro, Italy.
Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
Section Multiple Myeloma, Department of Internal Medicine V, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
Genes Development and Disease Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Karl Landsteiner University of Health Sciences, University Hospital Krems, Krems an der Donau, Austria.


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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