title: Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instability.
abstract: DNA licensing is a crucial process for chromosome replication control. Deregulation of the licensing factors Cdt1, Cdc6 and the licensing inhibitor geminin has been associated with DNA replication defects and chromosomal instability. We examined the expression of these factors, in mantle cell lymphoma (MCL) and non-neoplastic lymphoid samples, and analysed the potential role of their deregulation in genomic instability. Geminin, Cdt1 and Cdc6 were coordinately expressed in non-neoplastic tissues and most MCL in relationship to the proliferative activity of the cells. However, 6 (18%) tumours showed an unbalanced "licensing signature" characterized by a higher expression of Cdt1 and Cdc6 than the negative regulator geminin. Tumours with this unbalanced signature and p53/p14(ARF) alterations had significantly higher number of chromosome abnormalities than lymphomas with p53/p14(ARF) alterations but with a normal licensing signature. No aberrations of Cdct1, Cdc6, and geminin genes were detected in cases with unbalanced licensing. However, tumours with p53/ARF inactivation and unbalanced licensing signature had significantly higher cyclin D1 levels than tumours with normal licensing signature. These results suggest that an unbalanced mRNA expression of licensing regulatory genes may play a role in the pathogenesis of the chromosomal instability of a subset of MCL with inactivation of the p53/p14(ARF) pathway.
authors.affiliation: Genomics Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.forename: Silvia
authors.initials: S
authors.lastname: Bea
authors.forename: Verónica
authors.initials: V
authors.lastname: Fernández
authors.forename: Lluís
authors.initials: L
authors.lastname: Colomo
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations; D019938:Cyclin D1 / Q000235:genetics; D004261:DNA Replication; D064248:Geminin; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C103706:CDC6 protein, human; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; C577995:GMNN protein, human; D064248:Geminin; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1