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'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'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 = 0.0006) and cyclin A2 (p = 0.0006) positive cells that discriminated MCL with low cyclin D1 3'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'UTR is important because it seems to be associated with shorter overall survival.
(c) 2005 Wiley-Liss, Inc.