Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming
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Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming. / Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin; Wang, Hong Y; Cheng, Mangeng; Baldwin, Donald; Tobias, John W; Schuster, Stephen J; Andersen, Anders Woetmann; Zhang, Qian; Turner, Suzanne D; Ødum, Niels; Wasik, Mariusz A.
In: Journal of immunology (Baltimore, Md. : 1950), Vol. 191, No. 12, 15.12.2013, p. 6200-7.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming
AU - Marzec, Michal
AU - Halasa, Krzysztof
AU - Liu, Xiaobin
AU - Wang, Hong Y
AU - Cheng, Mangeng
AU - Baldwin, Donald
AU - Tobias, John W
AU - Schuster, Stephen J
AU - Andersen, Anders Woetmann
AU - Zhang, Qian
AU - Turner, Suzanne D
AU - Ødum, Niels
AU - Wasik, Mariusz A
PY - 2013/12/15
Y1 - 2013/12/15
N2 - 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.
AB - 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.
KW - CD4-Positive T-Lymphocytes
KW - Carbazoles
KW - Cell Line, Tumor
KW - Cell Transformation, Neoplastic
KW - Early Growth Response Protein 1
KW - Enzyme Activation
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Interleukin-2
KW - Lymphoma, T-Cell
KW - MAP Kinase Signaling System
KW - Molecular Mimicry
KW - Neoplasm Proteins
KW - Oncogene Proteins, Fusion
KW - Phenylurea Compounds
KW - Phosphorylation
KW - Protein Kinase Inhibitors
KW - Protein Processing, Post-Translational
KW - Protein-Tyrosine Kinases
KW - STAT3 Transcription Factor
KW - STAT5 Transcription Factor
KW - Signal Transduction
U2 - 10.4049/jimmunol.1300744
DO - 10.4049/jimmunol.1300744
M3 - Journal article
C2 - 24218456
VL - 191
SP - 6200
EP - 6207
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 12
ER -
ID: 117551667