Title | NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Ambrogio C, Martinengo C, Voena C, Tondat F, Riera L, Di Celle PFrancia, Inghirami G, Chiarle R |
Journal | Cancer Res |
Volume | 69 |
Issue | 22 |
Pagination | 8611-9 |
Date Published | 2009 Nov 15 |
ISSN | 1538-7445 |
Keywords | Adaptor Proteins, Signal Transducing, Animals, CD3 Complex, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Immunoblotting, Immunohistochemistry, Immunoprecipitation, Lymphoma, Large-Cell, Anaplastic, Membrane Proteins, Mice, Mice, Transgenic, Phenotype, Phosphoproteins, Polymerase Chain Reaction, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, T-Lymphocytes, Transcription, Genetic, ZAP-70 Protein-Tyrosine Kinase |
Abstract | 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 CD3epsilon, 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. |
DOI | 10.1158/0008-5472.CAN-09-2655 |
Alternate Journal | Cancer Res |
PubMed ID | 19887607 |
Grant List | R01-CA090773 / CA / NCI NIH HHS / United States |
Related Faculty:
Giorgio Inghirami, M.D.