Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although STAT5A and STAT5B have some nonredundant functional properties, their distinct contributions to carcinogenesis are not clearly defined. Here we report that STAT5A expression is selectively inhibited by DNA methylation of the STAT5A gene promoter region in cells expressing the oncogenic tyrosine kinase NPM1-ALK (also known as NPM-ALK). The DNA methylation is induced by NPM1-ALK itself via STAT3, and is associated with binding to the promoter of the gene encoding MeCP2 capping protein and with lack of binding of the STAT5A gene transcription activator SP1. Reversal of methylation by the DNA methyltransferase inhibitor 5'-aza-2'-deoxycytidine restores SP1 binding and STAT5A gene expression. Notably, the induced or exogenously expressed STAT5A protein binds to the enhancer and intron 14 of the NPM1-ALK gene and triggers selective suppression of NPM1-ALK expression. These results show that NPM1-ALK induces epigenetic silencing of STAT5A gene and that STAT5A protein can act as a key tumor suppressor by reciprocally inhibiting expression of NPM1-ALK.
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PMID:STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. 1792 9

Here we report that T-cell lymphoma cells carrying the NPM-ALK fusion protein (ALK(+) TCL) frequently express the cell-stimulatory receptor ICOS. ICOS expression in ALK(+) TCL is moderate and strictly dependent on the expression and enzymatic activity of NPM-ALK. NPM-ALK induces ICOS expression via STAT3, which triggers the transcriptional activity of the ICOS gene promoter. In addition, STAT3 suppresses the expression of miR-219 that, in turn, selectively inhibits ICOS expression. ALK(+) TCL cell lines display extensive DNA methylation of the CpG island located within intron 1, the putative enhancer region, of the ICOS gene, whereas cutaneous T-cell lymphoma cell lines, which strongly express ICOS, show no methylation of the island. Treatment of the ALK(+) TCL cell lines with DNA methyltransferase inhibitor reversed the CpG island methylation and augmented the expression of ICOS mRNA and protein. Stimulation of the ICOS receptor with anti-ICOS antibody or ICOS ligand-expressing B cells markedly enhanced proliferation of the ALK(+) TCL cells. These results demonstrate that NPM-ALK, acting through STAT3 as the gene transcriptional activator, induces the expression of ICOS, a cell growth promoting receptor. These data also show that the DNA methylation status of the intronic CpG island affects transcriptional activity of the ICOS gene and, consequently, modulates the concentration of the expressed ICOS protein.
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PMID:Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS. 2176 24

Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively. Correlative analysis indicated an adverse correlation between pSTAT3 and overall survival (OS). PTPN6, a tyrosine phosphatase and potential negative regulator of STAT3 activity, was suppressed in 62% of PTCL-NOS, 42% of AITL, 60% ALK-neg ALCL, and 86% of ALK-pos ALCL. Loss of PTPN6 combined with pSTAT3 positivity predicted an infwere considered significantferior OS in PTCL cases. In vitro treatment of TCL lines with azacytidine (aza), a DNA methyltransferase inhibitor (DNMTi), restored PTPN6 expression and decreased pSTAT3. Combining DNMTi with JAK3 inhibitor resulted in synergistic antitumor activity in SUDHL1 cell line. Overall, our results suggest that PTPN6 and activated STAT3 can be developed as prognostic markers, and the combination of DNMTi and JAK3 inhibitors as a novel treatment for patients with PTCL subtypes.
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PMID:Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma. 3042 May 93