HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

The CCAAT/enhancer-binding protein beta (C/EBP beta) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK(+)). Although ALK-mediated C/EBP beta transcriptional activation has been reported, C/EBP beta mRNA possesses U-and AU-rich domains in its 3'-untranslated region (3'-UTR) that might be privileged targets for posttranscriptional control in ALK(+) ALCLs. The purpose of this study was to explore this possibility. By using human ALCL-derived cells and a murine model of ALK-transformed cells, we show that the AU-binding protein HuR binds to the 3'-UTR of C/EBP beta mRNA, as previously reported in adipocytes, and that NPM-ALK enhances this interaction. Interaction between HuR and C/EBP beta mRNA impacts on C/EBP beta gene expression at both the mRNA and protein levels. Indeed, C/EBP beta mRNA stability following HuR silencing is reduced and reaches the value observed in ALK-inactivated cells. Remarkably, HuR expression is not modified by NPM-ALK, but its association with actively translating polysomes is dramatically increased in ALK+ cells. HuR/polysomes association diminishes when NPM-ALK activity is inhibited and is accompanied by a concomitant decrease of C/EBP beta mRNA translation. Finally, we show that HuR and NPM-ALK colocalized in cytoplasmic granules and HuR is phosphroylated on tyrosine residues in ALK(+) ALCL cells. Our study thus demonstrates that C/EBP beta is indeed regulated at the posttranscriptional level by HuR in ALK(+) cells, leading us to propose that part of NPM-ALK oncogenic properties relies on its ability to modify HuR properties in the cytoplasm and hence to alter expression of key actors of transformation. Mol Cancer Res; 9(4); 485-96. (C) 2011 AACR.