Role of ζ-Crystallin and Other AUBPs in Bcl-2 Over-Expression Occurring in B-cell CLLs.

We previously identified in the 3'UTR of bcl-2 mRNA an adenine + uracil-rich element (ARE) that regulates bcl-2 expression at the post-transcriptional level by interacting with specific AU-Binding Proteins (AUBPs). In most solid tumours and leukemias, bcl-2 is overexpressed without any obvious gene rearrangement or mutation, suggesting that it could depend on impaired ARE/AUBP interaction based post-transcriptional control. Investigating this possibility, we have recently disclosed a new bcl-2 AUBP, ζ-crystallin, which increased binding to the ARE of bcl-2 mRNA resulted in bcl-2 over-expression in T-cells of Acute Lymphocytic Leukemias (ALLs) patients as compared to T-cells from healthy donors. Here, we also show that ζ-crystallin and Bcl-2 protein levels are strictly co-related in B-cell Chronic Lymphocytic Leukemias (CLLs) and demonstrate that this is consequent to bcl-2 mRNA stabilization by ζ-crystallin, in a circuit involving shifting of other bcl-2 AUBPs. Our results clearly indicate that ζ-crystallin overproduction contributes to bcl-2 over-expression and thus to the onset of human B-cell CLLs. Acknowledgements: AIRC, MUR (PRIN 2008), Università di Firenze, ECR Firenze and FCR Lucca.