This Article Full Text (Online First [PDF]) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-2655v1 69/22/8611    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ambrogio, C. Articles by Chiarle, R. PubMed PubMed Citation Articles by Ambrogio, C. Articles by Chiarle, R.

NPM-ALK Oncogenic Tyrosine Kinase Controls T-Cell Identity by Transcriptional Regulation and Epigenetic Silencing in Lymphoma Cells

¹ Center for Experimental Research and Medical Studies and ² Department of Biomedical Sciences and Human Oncology, University of Torino; ³ ASO "San Giovanni Battista," Torino, Italy and ⁴ Department of Pathology and New York Cancer Center, New York University School of Medicine, New York, New York

Requests for reprints: Roberto Chiarle, Department of Biomedical Sciences and Human Oncology and Center for Experimental Research and Medical Studies, University of Torino, via Santena 7, 10126 Torino, Italy. Phone: 39-116-336860; Fax: 39-116-336887; E-mail: roberto.chiarle{at}unito.it.

Transformed cells in lymphomas usually maintain the phenotype of the postulated normal lymphocyte from which they arise. By contrast, anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma with aberrant phenotype because of the defective expression of the T-cell receptor and other T-cell–specific molecules for still undetermined mechanisms. The majority of ALCL carries the translocation t(2;5) that encodes for the oncogenic tyrosine kinase NPM-ALK, fundamental for survival, proliferation, and migration of transformed T cells. Here, we show that loss of T-cell–specific molecules in ALCL cases is broader than reported previously and involves most T-cell receptor–related signaling molecules, including CD3, ZAP70, LAT, and SLP76. We further show that NPM-ALK, but not the kinase-dead NPM-ALK^K210R, downregulated the expression of these molecules by a STAT3-mediated gene transcription regulation and/or epigenetic silencing because this downregulation was reverted by treating ALCL cells with 5-aza-2-deoxycytidine or by knocking down STAT3 through short hairpin RNA. Finally, NPM-ALK increased the methylation of ZAP70 intron 1-exon 2 boundary region, and both NPM-ALK and STAT3 regulated the expression levels of DNA methyltransferase 1 in transformed T cells. Thus, our data reveal that oncogene-deregulated tyrosine kinase activity controls the expression of molecules that determine T-cell identity and signaling. [Cancer Res 2009;69(22):8611–9]

Key Words: anaplastic lymphoma kinase • anaplastic large cell lymphoma • TCR • epigenetic silencing