Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3.

Abstract

The mechanisms of malignant cell transformation mediated by the oncogenic, chimeric nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) tyrosine kinase remain only partially understood. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells secrete IL-10 and TGF-beta and express FoxP3, indicating their T regulatory (Treg) cell phenotype. The secreted IL-10 suppresses proliferation of normal immune, CD3/CD28-stimulated peripheral blood mononuclear cells and enhances viability of the ALK+TCL cells. The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells. NPM/ALK, in turn, induces the phenotype through activation of its key signal transmitter, signal transducer and activator of transcription 3 (STAT3). These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4(+) T cells. These results also provide an additional rationale to therapeutically target the chimeric kinase and/or STAT3 in ALK+TCL.

• Authors: Monika Kasprzycka, Michal Marzec, Xiaobin Liu, Qian Zhang, Mariusz A Wasik
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 26 Pg. 9964-9 (Jun 27 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16766651 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CD28 Antigens
• FOXP3 protein, human
• Forkhead Transcription Factors
• Oncogene Proteins, Fusion
• Receptors, IgE
• STAT3 Transcription Factor
• STAT3 protein, human
• Transforming Growth Factor beta
• Interleukin-10
• p80(NPM-ALK) protein
• Protein-Tyrosine Kinases

Topics

• CD28 Antigens (analysis)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, immunology)
• Forkhead Transcription Factors (genetics, metabolism)
• Humans
• Immunosuppression Therapy
• Interleukin-10 (genetics, metabolism)
• Lymphoma, T-Cell (genetics, immunology)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Protein-Tyrosine Kinases (genetics, metabolism)
• Receptors, IgE (analysis)
• STAT3 Transcription Factor (metabolism)
• T-Lymphocytes, Regulatory (immunology)
• Transforming Growth Factor beta (genetics, metabolism)