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Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death

Oncogene volume 21, pages 1038–1047 (2002)Cite this article

Abstract

The anaplastic lymphoma kinase (ALK) gene is characteristically translocated in Anaplastic Large Cell Lymphomas (ALCL) and the juxtaposion of the ALK gene to multiple partners results in its constitutive protein tyrosine kinase activity. We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs. Furthermore, immunohistochemical studies demonstrate that among distinct human B and T cell lymphomas, activation of Stat3 nuclear translocation is uniquely associated with ALK expression. NPM-ALK also binds and activates Jak3; however, Jak3 is not required for Stat3 activation or for cell transformation in vitro. Moreover, src family kinases are not necessary for NPM-ALK-mediated Stat3 activation or transformation, suggesting that Stat3 may be phosphorylated directly by ALK. To evaluate relevant targets of ALK-activated Stat3, we investigated the regulation of the anti-apoptotic protein Bcl-xL and its role in cell survival in NPM-ALK positive cells. NPM-ALK expression caused enhanced Bcl-xL transcription, largely mediated by Stat3. Increased expression of Bcl-xL provided sufficient anti-apoptotic signals to protect cells from treatment with specific inhibitors of the Jaks/Stat pathway or the Brc-Abl kinase. These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells.

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Acknowledgements

We thank Drs R Jove and D Altieri for providing the Stat3β and the Bcl-xL promoter constructs and the anti-survivin Ab. A special thank to Drs I Guasparri and A Pesci for their technical assistance. This work was supported by NIH grant AI28900 and an AIRC grant.

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Author notes

  1. Alberto Zamo and Roberto Chiarle: A Zamo and R Chiarle contributed equally to this work

Authors and Affiliations

  1. Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Avenue, New York, 10016, NY, USA

    Alberto Zamo, Roberto Chiarle, Roberto Piva, Jennifer Howes, Yan Fan, David E Levy & Giorgio Inghirami

  2. Department of Pathology, University of Verona, Borgo Roma, Italy

    Alberto Zamo & Marco Chilosi

  3. Department of Pathology, University of Torino, Via Santena 7, Torino, Italy

    Roberto Chiarle

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  1. Alberto Zamo
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Correspondence to Giorgio Inghirami.

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Zamo, A., Chiarle, R., Piva, R. et al. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene 21, 1038–1047 (2002). https://doi.org/10.1038/sj.onc.1205152

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