The drive to generate multiple forms of oncogenic cyclin D1 transcripts in mantle cell lymphoma

Abstract Alternative polyadenylation is a rapidly emerging form of gene regulation, which in its simplest form, enables the generation of mRNA transcripts that code for the same protein but have 3′UTRs of different lengths and regulatory content. For oncogenes, shorter 3′UTRs would be preferred as a mechanism to evade miRNA regulation. The shortening of the 3′UTR of cyclin D1 in mantle cell lymphoma offers provocative insights into this process. Patient samples have revealed that 3′UTR shortening may occur due to mutations, or translocations that result in the generation of a chimeric 3′UTR. The truncated cyclin D1 3′UTRs resulting from alternative polyadenylation, use a premature canonical polyadenylation signal close to the stop codon that was generated either as a result of mutations or provided by another gene in the chimeric 3′UTR. The sequence of the polyadenylation signal in mantle cell lymphoma appears to be critical for 3′end formation of the cyclin D1 transcript. Shortening the 3′UTR allows cyclin D1 to potentially evade regulation by over 80 miRNAs that are predicted to bind to its full length 3′UTR

Discovery and characterization of a novel CCND1/MRCK gene fusion in mantle cell lymphoma

Abstract The t(11;14) translocation resulting in constitutive cyclin D1 expression is an early event in mantle cell lymphoma (MCL) transformation. Patients with a highly proliferative phenotype produce cyclin D1 transcripts with truncated 3′UTRs that evade miRNA regulation. Here, we report the recurrence of a novel gene fusion in MCL cell lines and MCL patient isolates that consists of the full protein coding region of cyclin D1 (CCND1) and a 3′UTR consisting of sequences from both the CCND1 3′UTR and myotonic dystrophy kinase-related Cdc42-binding kinase's (MRCK) intron one. The resulting CCND1/MRCK mRNA is resistant to CCND1-targeted miRNA regulation, and targeting the MRCK region of the chimeric 3′UTR with siRNA results in decreased CCND1 levels