title: The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment.
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.
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Fan
authors.affiliation: Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: M H
authors.initials: MH
authors.lastname: Bashari
authors.affiliation: University 'Magna Græcia' of Catanzaro, Catanzaro, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Morelli
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tonon
authors.affiliation: Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Malvestiti
authors.affiliation: Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Vallet
authors.affiliation: Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Jarahian
authors.affiliation: Section Multiple Myeloma, Department of Internal Medicine V, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Seckinger
authors.affiliation: Section Multiple Myeloma, Department of Internal Medicine V, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hose
authors.affiliation: Genes Development and Disease Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Bakiri
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C R
authors.initials: CR
authors.lastname: Ball
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sattler
authors.affiliation: Section Multiple Myeloma, Department of Internal Medicine V, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Genes Development and Disease Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: E F
authors.initials: EF
authors.lastname: Wagner
authors.affiliation: University 'Magna Græcia' of Catanzaro, Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Jaeger
authors.affiliation: Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.|Karl Landsteiner University of Health Sciences, University Hospital Krems, Krems an der Donau, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Podar
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D000069286:Bortezomib / Q000494:pharmacology; D049109:Cell Proliferation; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: C581727:JunB protein, human; D016328:NF-kappa B; D014157:Transcription Factors; D000069286:Bortezomib; D003907:Dexamethasone