Stat5a Is Epigenetically Silenced by Oncogenic Tyrosine Kinase NPM/ALK and Acts as Tumor Suppressor by Reciprocally Inhibiting Expression of NPM/ALK.

Although Stat5a and Stat5b exhibit some non-redundant functional properties, their distinct contributions to carcinogenesis are not clearly defined. Here we report that Stat5a expression is selectively inhibited by DNA methylation of the Stat5a gene promoter region in cells expressing an oncogenic tyrosine kinase NPM/ALK. The DNA methylation is induced by NPM/ALK itself by employing its key effector Stat3, and is associated with binding to the promoter of MeCP2 capping protein and lack of binding of the Stat5a transcription activator Sp-1. Reversal of the methylation by DNA methyltransferase inhibitor, 5′-aza-2-deoxycytidine, restores the Sp-1 binding and Stat5a expression. Strikingly, the induced or exogenously expressed Stat5a binds to enhancer and exon 14 of the NPM/ALK gene and triggers selective suppression of NPM/ALK expression. These results demonstrate that NPM/ALK induces epigenetic silencing of Stat5a and that Stat5a can act as key tumor suppressor by reciprocally inhibiting expression of NPM/ALK.