Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

The mechanisms of malignant cell transformation mediated by the oncogenic anaplastic lymphoma kinase (ALK) tyrosine kinase remain only partially understood. In this study, we report that T-cell lymphoma (TCL) cells carrying the nucleophosmin (NPM)/ALK fusion protein (ALK + TCL) strongly express hypoxia-induced factor 1 alpha (HIF1 alpha) mRNA, even under normoxic conditions, and markedly upregulate HIF1 alpha protein expression under hypoxia. HIF1 alpha expression is strictly dependent on the expression and enzymatic activity of NPM/ALK, as shown in BaF3 cells transfected with wild-type NPM/ALK and kinase-inactive NPM/ALK K210R mutant and by the inhibition of the NPM/ALK function in ALK + TCL cells by a small-molecule ALK inhibitor. NPM/ALK induces HIF1 alpha expression by upregulating its gene transcription through its key signal transmitter signal transducer and activator of transcription 3 (STAT3), which binds to the HIF1 alpha gene promoter as shown by the chromatin immunoprecipitation assay and is required for HIF1 alpha gene expression as demonstrated by its small interfering RNA-mediated depletion. In turn, depletion of HIF1 alpha increases mammalian target of rapamycin complex 1 activation, cell growth and proliferation and decreases vascular endothelial growth factor synthesis. These results identify a novel cell-transforming property of NPM/ALK, namely its ability to induce the expression of HIF1 alpha, a protein with an important role in carcinogenesis. These results also provide another rationale to therapeutically target NPM/ALK and STAT3 in ALK + TCL. Oncogene (2011) 30, 1372-1378; doi:10.1038/onc.2010.505; published online 22 November 2010