Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming.
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.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Michal
M
Marzec
Krzysztof
K
Halasa
Xiaobin
X
Liu
Hong Y
HY
Wang
Mangeng
M
Cheng
Donald
D
Baldwin
John W
JW
Tobias
Stephen J
SJ
Schuster
Anders
A
Woetmann
Qian
Q
Zhang
Suzanne D
SD
Turner
Niels
N
Ødum
Mariusz A
MA
Wasik
D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000201:enzymology* / Q000235:genetics; D020935:MAP Kinase Signaling System; D018716:Molecular Mimicry; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000502:physiology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
C540057:CEP 14083; D002227:Carbazoles; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D007376:Interleukin-2; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases