Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Qian Zhang1,
  2. HongYi Wang2,
  3. Kanchan Kantekure1,
  4. Jennifer C. Paterson3,
  5. Xiaobin Liu1,
  6. Andras Schaffer4,
  7. Chrystal Paulos5,
  8. Michael C. Milone1,
  9. Niels Odum6,
  10. Suzanne Turner7,
  11. Teresa Marafioti3, and
  12. Mariusz A. Wasik1,*
  1. 1 Departments of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States;
  2. 2 Departments of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, Ukraine;
  3. 3 Department of Histopathology, University College London, London, United Kingdom;
  4. 4 Department of Dermatology, University of Pennsylvania, Philadelphia, PA, United States;
  5. 5 Department of Microbiology, Immunology, and Surgery, Medical University of South Carolina, Charleston, SC, United States;
  6. 6 Institute of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
  7. 7 Department of Pathology, University of Cambridge, Cambridge, United Kingdom
  1. * Corresponding author; email: wasik{at}mail.med.upenn.edu

Abstract

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 CTCL 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.

  • Submitted January 27, 2011.
  • Accepted June 26, 2011.