title: BCL-B (BCL2L10) is overexpressed in patients suffering from multiple myeloma (MM) and drives an MM-like disease in transgenic mice.
abstract: Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that Eµ-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease. Indeed, with age, Eµ-bcl-b transgenic mice develop the characteristic features of human MM, including bone malignant plasma cell infiltration, a monoclonal immunoglobulin peak, immunoglobulin deposit in renal tubules, and highly characteristic bone lytic lesions. In addition, the tumors are serially transplantable in irradiated wild-type mice, underlying the tumoral origin of the disease. Eµ-bcl-b plasmocytes show increased expression of a panel of genes known to be dysregulated in human MM pathogenesis. Treatment of Eµ-bcl-b mice with drugs currently used to treat patients such as melphalan and VELCADE efficiently kills malignant plasmocytes in vivo. Finally, we find that Bcl-B is overexpressed in plasmocytes from MM patients but neither in MGUS patients nor in healthy individuals, suggesting that Bcl-B may drive MM. These findings suggest that Bcl-B could be an important factor in MM disease and pinpoint Eµ-bcl-b mice as a pertinent model to validate new therapies in MM.
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Mohamed-Amine
authors.identifier: 0000-0001-5877-3397
authors.initials: MA
authors.lastname: Hamouda
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Arnaud
authors.identifier: 0000-0001-5062-8048
authors.initials: A
authors.lastname: Jacquel
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Guillaume
authors.identifier: 0000-0002-6350-2222
authors.initials: G
authors.lastname: Robert
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Service de Médecine Interne, Centre Hospitalier Universitaire de Nice, 06003 Nice, France.
authors.forename: Valentine
authors.initials: V
authors.lastname: Richez
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Romeo
authors.initials: R
authors.lastname: Cassel
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
authors.forename: Nina
authors.initials: N
authors.lastname: Fenouille
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, INSERM U1104, Centre National de la Recherche Scientifique (CNRS) UMR 7280, 13288 Marseille, France.
authors.forename: Sandrine
authors.identifier: 0000-0003-2187-1959
authors.initials: S
authors.lastname: Roulland
authors.affiliation: Team 7, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Gilleron
authors.affiliation: Team 4, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France.
authors.forename: Emmanuel
authors.identifier: 0000-0001-7529-4187
authors.initials: E
authors.lastname: Griessinger
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Alix
authors.identifier: 0000-0002-4551-7746
authors.initials: A
authors.lastname: Dubois
authors.affiliation: Team 8, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Diogo
authors.identifier: 0000-0002-1699-747X
authors.initials: D
authors.lastname: Goncalves
authors.affiliation: Team 11, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Mallavialle
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Pascal
authors.identifier: 0000-0002-5848-6053
authors.initials: P
authors.lastname: Colosetti
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchetti
authors.affiliation: Team 10, INSERM U892, 44007 Nantes, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Amiot
authors.affiliation: Team 10, INSERM U892, 44007 Nantes, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gomez-Bougie
authors.affiliation: Université de Nice Sophia-Antipolis, 06000 Nice, France UMR 7277, 06108 Nice, France.
authors.forename: Nathalie
authors.identifier: 0000-0002-9995-6699
authors.initials: N
authors.lastname: Rochet
authors.affiliation: Team 11, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France.
authors.forename: Marcel
authors.identifier: 0000-0003-2094-559X
authors.initials: M
authors.lastname: Deckert
authors.affiliation: Cancer Research Center of Toulouse, UMR 1037, INSERM-Université Toulouse III Paul Sabatier (UPS)-CNRS, 31037 Toulouse, France.
authors.forename: Herve
authors.initials: H
authors.lastname: Avet-Loiseau
authors.affiliation: Service d'Anatomopathologie, Centre Hospitalier Universitaire de Nice, 06003 Nice, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Universitaire de Nice, 06003 Nice, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Karsenti
authors.affiliation: Service de Médecine Interne, Centre Hospitalier Universitaire de Nice, 06003 Nice, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Jeandel
authors.affiliation: Université de Nice Sophia-Antipolis, 06000 Nice, France CNRS UMR 7370, 06108 Nice, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Blin-Wakkach
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, INSERM U1104, Centre National de la Recherche Scientifique (CNRS) UMR 7280, 13288 Marseille, France.
authors.forename: Bertrand
authors.identifier: 0000-0002-4644-5617
authors.initials: B
authors.lastname: Nadel
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France Service d'Hématologie Clinique, Centre Hospitalier Universitaire de Nice, 06003 Nice, France.
authors.forename: Thomas
authors.identifier: 0000-0002-6745-1127
authors.initials: T
authors.lastname: Cluzeau
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Kenneth C
authors.identifier: 0000-0002-6418-0886
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Service de Médecine Interne, Centre Hospitalier Universitaire de Nice, 06003 Nice, France.
authors.forename: Jean-Gabriel
authors.initials: JG
authors.lastname: Fuzibet
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Patrick
authors.identifier: 0000-0002-2481-8275
authors.initials: P
authors.lastname: Auberger
authors.affiliation: Team 2, Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Université de Nice Sophia-Antipolis, 06000 Nice, France Equipe Labellisée par la Ligue Nationale Contre le Cancer, 75013 Paris, France fluciano@unice.fr.
authors.forename: Frederic
authors.identifier: 0000-0001-9253-4998
authors.initials: F
authors.lastname: Luciano
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D006942:Hypergammaglobulinemia / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000209:etiology* / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology*; D053668:Syndecan-1 / Q000032:analysis; D051020:bcl-X Protein / Q000502:physiology
chemical_list: C117144:BCL2-like 10 protein; D019253:Proto-Oncogene Proteins c-bcl-2; D053668:Syndecan-1; D051020:bcl-X Protein