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

Michal Marzec; Krzysztof Halasa; Xiaobin Liu; Hong Y Wang; Mangeng Cheng; Donald Baldwin; John W Tobias; Stephen J Schuster; Anders Woetmann Andersen; Qian Zhang; Suzanne D Turner; Niels Ødum; Mariusz A Wasik

doi:10.4049/jimmunol.1300744

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

Michal Marzec, Krzysztof Halasa, Xiaobin Liu, Hong Y Wang, Mangeng Cheng, Donald Baldwin, John W Tobias, Stephen J Schuster, Anders Woetmann Andersen, Qian Zhang, Suzanne D Turner, Niels Ødum, Mariusz A Wasik

13 Citationer (Scopus)

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 ALK2 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.

Originalsprog	Engelsk
Tidsskrift	Journal of immunology (Baltimore, Md. : 1950)
Vol/bind	191
Udgave nummer	12
Sider (fra-til)	6200-7
Antal sider	8
ISSN	0022-1767
DOI	https://doi.org/10.4049/jimmunol.1300744
Status	Udgivet - 15 dec. 2013

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10.4049/jimmunol.1300744

Citationsformater

Marzec, M., Halasa, K., Liu, X., Wang, H. Y., Cheng, M., Baldwin, D., Tobias, J. W., Schuster, S. J., Andersen, A. W., Zhang, Q., Turner, S. D., Ødum, N., & 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

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 et al.
I: Journal of immunology (Baltimore, Md. : 1950), Bind 191, Nr. 12, 15.12.2013, s. 6200-7.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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), bind 191, nr. 12, s. 6200-7. https://doi.org/10.4049/jimmunol.1300744

@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 ALK2 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 = dec,

day = "15",

doi = "10.4049/jimmunol.1300744",

language = "English",

volume = "191",

pages = "6200--7",

journal = "Journal of immunology (Baltimore, Md. : 1950)",

issn = "0022-1767",

publisher = "American Association of Immunologists",

number = "12",

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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 ALK2 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 ALK2 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

SN - 0022-1767

VL - 191

SP - 6200

EP - 6207

JO - Journal of immunology (Baltimore, Md. : 1950)

JF - Journal of immunology (Baltimore, Md. : 1950)

IS - 12

ER -

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

Abstract

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