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Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

Oncogene volume 30, pages 1372–1378 (2011)Cite this article

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Abstract

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 1α (HIF1α) mRNA, even under normoxic conditions, and markedly upregulate HIF1α protein expression under hypoxia. HIF1α 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 HIF1α expression by upregulating its gene transcription through its key signal transmitter signal transducer and activator of transcription 3 (STAT3), which binds to the HIF1α gene promoter as shown by the chromatin immunoprecipitation assay and is required for HIF1α gene expression as demonstrated by its small interfering RNA-mediated depletion. In turn, depletion of HIF1α 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 HIF1α, a protein with an important role in carcinogenesis. These results also provide another rationale to therapeutically target NPM/ALK and STAT3 in ALK+ TCL.

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Acknowledgements

This study was supported in part by grants from the National Cancer Institute- R01-CA89194 and R01-CA96856.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    M Marzec, X Liu, Y Yang, T Pasha, K Kantekure, P Zhang & M A Wasik

  2. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA

    W Wong

  3. Abramson Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA

    W Wong

  4. Institute of Molecular Biology, University of Copenhagen, Copenhagen, Denmark

    A Woetmann & N Odum

  5. Cephalon Inc., West Chester, PA, USA

    M Cheng

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  1. M Marzec
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  2. X Liu
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  10. N Odum
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  11. M A Wasik
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Correspondence to M A Wasik.

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Marzec, M., Liu, X., Wong, W. et al. Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA. Oncogene 30, 1372–1378 (2011). https://doi.org/10.1038/onc.2010.505

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