Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instability

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DNA licensing is a crucial process for chromosome replication control. Deregulation of the licensing factorsCdt1,Cdc6and the licensing inhibitorgemininhas 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,Cdt1andCdc6were 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 ofCdt1andCdc6than the negative regulatorgeminin. Tumours with this unbalanced signature andp53/p14ARFalterations had significantly higher number of chromosome abnormalities than lymphomas withp53/p14ARFalterations but with a normal licensing signature. No aberrations ofCdct1,Cdc6, andgeminingenes 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 thep53/p14ARFpathway.

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