title: Addiction of MYCN amplified tumours to B-MYB underscores a reciprocal regulatory loop.
abstract: MYCN is a member of the MYC family of oncoproteins frequently amplified or overexpressed in aggressive, paediatric tumours of the nervous system. In this study we have identified the gene B-MYB, encoding the transcription factor also known as MYBL2, as a downstream target of MYCN. Using multiple in silico databases we show that expression of B-MYB significantly correlates with that of MYCN in neuroblastoma patients. MYCN binds to and activates the B-MYB gene in vivo and in vitro. Blunting B-MYB expression by RNA interference causes reduced proliferation of MYCN amplified, but not MYCN-non amplified, neuroblastoma cell lines, indicating that tumour cells are addicted to B-MYB in a MYCN dependent manner. Notably, B-MYB binds in vivo to the MYCN amplicon and is required for its expression. We conclude that MYCN and B-MYB are engaged in a reciprocal regulatory loop whose pharmacological targeting could be beneficial to patients with the aggressive forms of cancer in which MYCN is amplified.
authors.affiliation: Molecular Haeamatology and Cancer Biology Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gualdrini
authors.affiliation: Molecular Haeamatology and Cancer Biology Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Daisy
authors.initials: D
authors.lastname: Corvetta
authors.affiliation: Molecular Haeamatology and Cancer Biology Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cantilena
authors.affiliation: Molecular Haeamatology and Cancer Biology Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Olesya
authors.initials: O
authors.lastname: Chayka
authors.affiliation: ENEA Research Center, Laboratory of Radiation Biology and Biomedicine Via Anguillarese, 301, 00123 S. Maria di Galeria, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tanno
authors.affiliation: ENEA Research Center, Laboratory of Radiation Biology and Biomedicine Via Anguillarese, 301, 00123 S. Maria di Galeria, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Raschellà
authors.affiliation: Molecular Haeamatology and Cancer Biology Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Arturo
authors.initials: A
authors.lastname: Sala
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C064352:MYBL2 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D015534:Trans-Activators