NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells

Cancer Res. 2009 Nov 15;69(22):8611-9. doi: 10.1158/0008-5472.CAN-09-2655. Epub 2009 Nov 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Animals
  • CD3 Complex / biosynthesis
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing / physiology*
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Immunoprecipitation
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / metabolism
  • Membrane Proteins / biosynthesis
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Phosphoproteins / biosynthesis
  • Polymerase Chain Reaction
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Antigen, T-Cell / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / biosynthesis
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / physiology
  • Transcription, Genetic
  • ZAP-70 Protein-Tyrosine Kinase / biosynthesis


  • Adaptor Proteins, Signal Transducing
  • CD3 Complex
  • CD3E protein, human
  • LAT protein, human
  • Membrane Proteins
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • SLP-76 signal Transducing adaptor proteins
  • STAT3 Transcription Factor
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human