The role of transcript variants of cyclin D1 in cancer biology is unclear. Most tumors with high levels of cyclin D1 express 2 transcripts due to alternative splicing: one full-length transcript of 4.4 kb and one short transcript of approximately 1.7 kb. The short transcript lacks part of the 3 0 UTR region regulating mRNA stability and has a longer half-life. In our study, the contribution of each of these mRNAs to gene expression and cell proliferation has been investigated in mantle cell lymphoma (MCL), a B cell lymphoma characterized by a specific gene translocation resulting in enhanced expression of cyclin D1. A subset of MCL tumors with low levels of the long cyclin D1 transcript (cyclin D1 3 0 UTR) was identified by quantitative PCR and by oligonucleotide array hybridization. This tumor-subset had 3.4-fold higher levels of the short form of cyclin D1 mRNA (p < 0.0001) and had higher expression of cyclin D1 protein. Gene expression analysis identified a number of cell-cycle regulatory genes as upregulated. There was a significant difference in frequencies of cyclin B1 (p 5 0.0006) and cyclin A2 (p 5 0.0006) positive cells that discriminated MCL with low cyclin D1 3 0 UTR from other highly proliferative MCL. Among differentially expressed genes, there was a highly upregulated gene with homology to the group of cell-cycle promoting E2F transcription partners, E2F_TDP5. Several of the upregulated genes, such as TOP2A, AURORA A and RRM2 may influence a response to therapy. Identification of MCL with low cyclin D1 3 0 UTR is important because it seems to be associated with shorter overall survival. ' 2005 Wiley-Liss, Inc.Key words: mantle cell lymphoma; cyclins; CCND1 3 0 UTR; proliferation; expression profiling; micro array In most tumors demonstrating inappropriately high levels of cyclin D1 gene expression, 2 cyclin D1 transcripts are present due to alternative polyadenylation: one full-length transcript of 4.4 kb and one shorter transcript of 1.7 kb.1 The short transcript lacks the 3 0 -UTR, AU-rich, sequences of the mRNA containing destabilizing elements (Fig. 1). The role of long and short cyclin D1 transcript in cancer biology is unclear. The aberrant expression of cyclin leads to a disturbed cell cycle regulation; cyclin D1 binds to cyclin dependent kinase Cdk4 and initiates phosphorylation of Rb resulting in the release of E2F and transcriptional activation of S-phase genes.2 It has also been suggested that cyclin D1 sequesters Cip/Kip cell cycle inhibitors such as p21waf1 and p27Kip1 from cyclinE/Cdk2 complexes thereby relieving the inhibitory effect and further inducing progression toward S-phase.3 In addition to the cell cycle related functions, cyclin D1 is a transcriptional activator 2 that induces gene expression not only via the E2F transcription factors but also by modifying the effects of transcription factors such as C/EBP beta 4 and other targets, not yet wellcharacterized.
2Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma of B cell origin that expresses the B cell markers CD20 and CD7...