Journal
CANCER RESEARCH
Volume 69, Issue 22, Pages 8611-8619Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-2655
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Funding
- Ministero dell'Universita e Ricerca Scientifica
- Associazione Italiana per la Ricerca sul Cancro
- Compagnia di San Paolo, Torino (Progetto Oncologia)
- Regione Piemonte (Ricerca Sanitaria Finalizzata and Ricerca Scientifica)
- European Union [LSHB-CT-2004-005276]
- NIH [R01-CA090773]
- Fondazione Cassa di Risparmio di Torino
- Foridazione Guido Berlucchi per la Ricerca sul Cancro
- Fondazione Italiana per la Ricerca sul Cancro fellowship
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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 epsilon, 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]
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