Pax-5 Protein Expression Is Regulated by Transcriptional 3'UTR Editing.

The gene encodes a transcription factor that is essential for B-cell commitment and maturation. However, deregulation is associated with various cancer lesions, notably hematopoietic cancers. Mechanistically, studies have characterized genetic alterations within the -5 locus that result in either dominant oncogenic function or haploinsufficiency-inducing mutations leading to oncogenesis. Apart from these mutations, some examples of aberrant expression cannot be associated with genetic alterations. In the present study, we set out to elucidate potential alterations in post-transcriptional regulation of expression and establish that transcript editing represents an important means to aberrant expression. Upon the profiling of mRNA in leukemic cells, we found that the 3'end of the transcript is submitted to alternative polyadenylation (APA) and alternative splicing events. Using rapid amplification of cDNA ends (3'RACE) from polysomal fractions, we found that 3' untranslated region (UTR) shortening correlates with increased ribosomal occupancy for translation. These observations were also validated using reporter gene assays with truncated 3'UTR regions cloned downstream of a luciferase gene. We also showed that 3'UTR editing has direct repercussions on regulatory elements such as miRNAs, which in turn impact Pax-5 protein expression. More importantly, we found that advanced staging of various hematopoietic cancer lesions relates to shorter 3'UTRs. Altogether, our findings identify novel molecular mechanisms that account for aberrant expression and function of the oncogene in cancer cells. These findings also present new avenues for strategic intervention in -mediated cancers.