TY - JOUR

T1 - Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS

AU - Zhang, Qian

AU - Wang, HongYi

AU - Kantekure, Kanchan

AU - Paterson, Jennifer C.

AU - Liu, Xiaobin

AU - Schaffer, Andreas

AU - Paulos, Chrystal

AU - Milone, Michael C.

AU - Ødum, Niels

AU - Turner, Suzanne

AU - Marafioti, Teresa

AU - Wasik, Mariusz A.

PY - 2011/9/15

Y1 - 2011/9/15

N2 - 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.

AB - 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.

KW - Adult

KW - Base Sequence

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - CpG Islands

KW - DNA Methylation

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Inducible T-Cell Co-Stimulator Protein

KW - Jurkat Cells

KW - Models, Biological

KW - Oncogenes

KW - Protein Kinase Inhibitors

KW - Protein-Tyrosine Kinases

U2 - 10.1182/blood-2011-01-332916

DO - 10.1182/blood-2011-01-332916

M3 - Journal article

C2 - 21765024

VL - 118

SP - 3062

EP - 3071

JO - Blood

JF - Blood

SN - 0006-4971

IS - 11

ER -