Bcl-2 Over-Expression in Human T-Cell Acute LymphocyticLeukemias is Consequent to mRNA Stabilization by Increased Binding to Zeta-Crystallin, a New Bcl-2 ARE-Binding Protein

We previously revealed a mechanism of post-transcriptional control of bcl-2 expression based on interactions between an AU-rich element (ARE) of its 3’ UTR and AU-binding proteins (AUBPs) finely modulating bcl-2 mRNA decay. In acute lymphocytic leukemias (ALLs), bcl-2 is very often over-expressed in the absence of evident gene rearrangements accounting for enhanced bcl-2 transcription, which suggests that deregulated post-transcriptional control could be involved. Here, using three bcl-2 over-expressing ALL T-cell lines, we first identified zeta-crystallin as a new bcl-2 AUBP and demonstrated that bcl-2 over-expression resulted from its three-fold increased binding to mRNA of ALL cell lines than of PHA activated Tlymphocytes. Two bits of symmetric evidence demonstrated that bcl-2 and ζ- crystallin expression are causally interrelated. Bcl-2 mRNA stability was significantly decreased following silencing of zeta-crystallin with siRNA, while it increased following cell transfection with recombinant zeta-crystallin. The relevance of this pathogenetic mechanism in human pediatric T-cell ALLs has been confirmed with highly significant data.