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Lymphoma

Aberrant expression of IL-22 receptor 1 and autocrine IL-22 stimulation contribute to tumorigenicity in ALK+ anaplastic large cell lymphoma

Leukemia volume 22, pages 1595–1603 (2008)Cite this article

Abstract

One of the characteristic features of anaplastic lymphoma kinase (ALK)+, anaplastic large cell lymphoma (ALK+ALCL) is the constitutive activation of signal transducers and activators of transcription-3 (STAT3), a defect believed to be important for the pathogenesis of these tumors. In this report, we describe the existence of an autocrine stimulatory loop involving interleukin-22 (IL-22) that contributes to STAT3 activation and tumorigenicity of ALK+ALCL. The IL-22 receptor, a heterodimer composed of IL-22R1 and IL-10R2, was expressed in all ALK+ALCL cell lines and tumors examined. The expression of IL-22R1 in ALK+ALCL is aberrant, as this protein is absent in benign lymphocytes. Although ALK+ALCL cells produce endogenous IL-22, addition of recombinant IL-22 to ALK+ALCL cell lines significantly increased STAT3 activation, cell proliferation and colony formation in soft agar. Opposite biological effects were observed in cells treated with recombinant IL-22 binding protein (a naturally occurring IL-22 decoy) or IL-22-neutralizing antibody. Nucleophosmin (NPM)-ALK, the characteristic fusion gene oncoprotein expressed in ALK+ALCL, directly contributes to the aberrant expression of IL-22R1, as transfection of NPM-ALK in Jurkat cells-induced IL-22R1 expression and IL-22-mediated STAT3 activation. To conclude, for the first time, we demonstrate the importance of the IL-22 autocrine pathway in a lymphoid malignancy, and reveal yet another novel function of NPM-ALK.

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Acknowledgements

This study is supported by operating research grants from the Alberta Cancer Foundation, Canadian Cancer Society/National Cancer Institute of Canada and the Canadian Institute for Health Research awarded to RL. PG is a research fellow supported by the Lymphoma Foundation of Canada. MA is a clinical research fellowship supported by the Canadian Cancer Society and the National Cancer Institute of Canada. HMA is a recipient of the University of Texas MD Anderson Physician Scientist Program Award and also a K08 award from the National Cancer Institute (CA114395).

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada

    J Dien Bard, P Gelebart, M Anand & R Lai

  2. Department of Hematopathology, the University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    H M Amin

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  1. J Dien Bard
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Correspondence to R Lai.

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Bard, J., Gelebart, P., Anand, M. et al. Aberrant expression of IL-22 receptor 1 and autocrine IL-22 stimulation contribute to tumorigenicity in ALK+ anaplastic large cell lymphoma. Leukemia 22, 1595–1603 (2008). https://doi.org/10.1038/leu.2008.129

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