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STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression

Nature Medicine volume 13, pages 1341–1348 (2007)Cite this article

Abstract

Although STAT5A and STAT5B have some nonredundant 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 the oncogenic tyrosine kinase NPM1-ALK (also known as NPM-ALK). The DNA methylation is induced by NPM1-ALK itself via STAT3, and is associated with binding to the promoter of the gene encoding MeCP2 capping protein and with lack of binding of the STAT5A gene transcription activator SP1. Reversal of methylation by the DNA methyltransferase inhibitor 5′-aza-2′-deoxycytidine restores SP1 binding and STAT5A gene expression. Notably, the induced or exogenously expressed STAT5A protein binds to the enhancer and intron 14 of the NPM1-ALK gene and triggers selective suppression of NPM1-ALK expression. These results show that NPM1-ALK induces epigenetic silencing of STAT5A gene and that STAT5A protein can act as a key tumor suppressor by reciprocally inhibiting expression of NPM1-ALK.

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Figure 1: Lack of STAT5A expression in NPM1-ALK+ T cells.
Figure 2: Methylation of CpG island within STAT5A gene promoter region in NPM1-ALK+ T cells.
Figure 3: Demethylation of STAT5A promoter region results in recruitment of SP1 to the promoter and expression of STAT5A mRNA and protein.
Figure 4: STAT5A binds to the enhancer of the NPM1-ALK gene and downregulates expression of the gene.
Figure 5: NPM1-ALK promotes epigenetic silencing of the STAT5A gene.
Figure 6: STAT3-mediated inhibition of STAT5A gene expression and effect of DNMT inhibition on growth of NPM1-ALK+ T cells.

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Acknowledgements

This work was supported in part by US National Cancer Institute grants R01-CA89194 and R01-CA96856.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, 19104-4283, Pennsylvania, USA

    Qian Zhang, Hong Y Wang, Xiaobin Liu & Mariusz A Wasik

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  1. Qian Zhang
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Correspondence to Qian Zhang or Mariusz A Wasik.

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Zhang, Q., Wang, H., Liu, X. et al. STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nat Med 13, 1341–1348 (2007). https://doi.org/10.1038/nm1659

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