NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells.
NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells.
复制标题
NPM-Alk-Alk致癌酪氨酸激酶通过转录调控和淋巴瘤细胞的表观遗传沉默来控制T细胞的身份。
DOI：
10.1158/0008-5472.can-09-2655
复制
发表时间：
2009-11-15
期刊：
影响因子：
11.2
通讯作者：
Chiarle R
中科院分区：
文献类型：
--
作者：
Ambrogio C;Martinengo C;Voena C;Tondat F;Riera L;di Celle PF;Inghirami G;Chiarle R
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 (TCR) 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 previously reported and involves most TCR-related signalling molecules, including CD3ε, ZAP70, LAT and SLP76. We further demonstrate that NPM-ALK, but not the kinase dead NPM-ALKK210R, down-regulated the expression of these molecules by a STAT3-mediated gene transcription regulation and/or epigenetic silencing since this down-regulation was reverted by treating ALCL cells with 5-aza-2′-deoxycytidine or by knocking-down STAT3 through sh-RNA. Finally, NPM-ALK increased the methylation of ZAP-70 intron1-exon2 boundary region, and both NPM-ALK and STAT3 regulated the expression levels of DNA methyltransferase 1 (DNMT1) 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 signalling.
