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 journalJournal articleResearchpeer-review

Harvard

Marzec, M, Halasa, K, Liu, X, Wang, HY, Cheng, M, Baldwin, D, Tobias, JW, Schuster, SJ, Andersen, AW, Zhang, Q, Turner, SD, Ødum, N & Wasik, MA 2013, 'Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming', Journal of immunology (Baltimore, Md. : 1950), vol. 191, no. 12, pp. 6200-7. https://doi.org/10.4049/jimmunol.1300744

APA

Marzec, M., Halasa, K., Liu, X., Wang, H. Y., Cheng, M., Baldwin, D., ... Wasik, M. A. (2013). Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming. Journal of immunology (Baltimore, Md. : 1950), 191(12), 6200-7. https://doi.org/10.4049/jimmunol.1300744

Vancouver

Marzec M, Halasa K, Liu X, Wang HY, Cheng M, Baldwin D et al. Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming. Journal of immunology (Baltimore, Md. : 1950). 2013 Dec 15;191(12):6200-7. https://doi.org/10.4049/jimmunol.1300744

Author

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. / Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming. In: Journal of immunology (Baltimore, Md. : 1950). 2013 ; Vol. 191, No. 12. pp. 6200-7.

Bibtex

@article{9b577f42e0194f8aba3485d400739235,
title = "Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming",
abstract = "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.",
keywords = "CD4-Positive T-Lymphocytes, Carbazoles, Cell Line, Tumor, Cell Transformation, Neoplastic, Early Growth Response Protein 1, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Interleukin-2, Lymphoma, T-Cell, MAP Kinase Signaling System, Molecular Mimicry, Neoplasm Proteins, Oncogene Proteins, Fusion, Phenylurea Compounds, Phosphorylation, Protein Kinase Inhibitors, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, STAT3 Transcription Factor, STAT5 Transcription Factor, Signal Transduction",
author = "Michal Marzec and Krzysztof Halasa and Xiaobin Liu and Wang, {Hong Y} and Mangeng Cheng and Donald Baldwin and Tobias, {John W} and Schuster, {Stephen J} and Andersen, {Anders Woetmann} and Qian Zhang and Turner, {Suzanne D} and Niels {\O}dum and Wasik, {Mariusz A}",
year = "2013",
month = "12",
day = "15",
doi = "10.4049/jimmunol.1300744",
language = "English",
volume = "191",
pages = "6200--7",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "12",

}

RIS

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