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 Citations (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.

Original language	English
Journal	Journal of immunology (Baltimore, Md. : 1950)
Volume	191
Issue number	12
Pages (from-to)	6200-7
Number of pages	8
ISSN	0022-1767
DOIs	https://doi.org/10.4049/jimmunol.1300744
Publication status	Published - 15 Dec 2013

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

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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.

In: Journal of immunology (Baltimore, Md. : 1950), Vol. 191, No. 12, 15.12.2013, p. 6200-7.

Research output: Contribution to journal › Journal article › Research › 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), vol. 191, no. 12, pp. 6200-7. https://doi.org/10.4049/jimmunol.1300744

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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.",

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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}",

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doi = "10.4049/jimmunol.1300744",

language = "English",

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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

JF - Journal of Immunology

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

Keywords

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