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

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 -