Aberrant expression of IL-22 receptor 1 and autocrine IL-22 stimulation contribute to tumorigenicity in ALK anaplastic large cell lymphoma
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 repor...
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Veröffentlicht in: | Leukemia 2008-08, Vol.22 (8), p.1595-1603 |
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Sprache: | eng |
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Zusammenfassung: | 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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ISSN: | 0887-6924 1476-5551 |
DOI: | 10.1038/leu.2008.129 |