Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming

J Immunol. 2013 Dec 15;191(12):6200-7. doi: 10.4049/jimmunol.1300744. Epub 2013 Nov 11.


Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity of nucleophosmin (NPM)/ALK chimeric protein, the dominant form of ALK expressed in T cell lymphomas (TCLs), closely resembles cell activation induced by IL-2, the key cytokine supporting growth and survival of normal CD4(+) T lymphocytes. Direct comparison of gene expression by ALK(+) TCL cells treated with an ALK inhibitor and IL-2-dependent ALK(-) TCL cells stimulated with the cytokine revealed a very similar, albeit inverse, gene-regulation pattern. Depending on the analysis method, up to 67% of the affected genes were modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT- and IL-2-signaling pathways topped the list of pathways identified as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes-CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4-was confirmed at the protein level. In both ALK(+) TCL and IL-2-stimulated ALK(-) TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly by the STAT5 and STAT3 transcription factors, whereas transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms the target CD4(+) T lymphocytes, at least in part, by using the pre-existing, IL-2-dependent signaling pathways.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology*
  • Carbazoles / pharmacology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Early Growth Response Protein 1 / biosynthesis
  • Early Growth Response Protein 1 / genetics
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-2 / physiology*
  • Lymphoma, T-Cell / enzymology*
  • Lymphoma, T-Cell / genetics
  • MAP Kinase Signaling System
  • Molecular Mimicry
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / physiology*
  • Phenylurea Compounds / pharmacology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology*
  • STAT3 Transcription Factor / physiology
  • STAT5 Transcription Factor / physiology
  • Signal Transduction / genetics


  • CEP 14083
  • Carbazoles
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Interleukin-2
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases

Associated data

  • GEO/GSE50803
  • GEO/GSE8685