Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3.
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.
Kasprzycka
Monika
M
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA.
Marzec
Michal
M
Liu
Xiaobin
X
Zhang
Qian
Q
Wasik
Mariusz A
MA
D018106:CD28 Antigens / Q000032:analysis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000276:immunology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D018106:CD28 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015514:Oncogene Proteins, Fusion; D017455:Receptors, IgE; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases