Upregulation of the CDC25A phosphatase down-stream of the NPM/ALK oncogene participates to anaplastic large cell lymphoma enhanced proliferation

Here, we demonstrate that the expression of the dual specificity phosphatase CDC25A, a key regulator of cell cycle progression, is deregulated in Ba/F3 cells expressing the oncogenic protein NPM/ALK and in human cell lines derived from NPM/ALK-positive anaplastic large cell lymphomas (ALCL). Both tr...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2009-05, Vol.8 (9), p.1373-1379
Main Authors: Fernandez-Vidal, Anne, Mazars, Anne, Gautier, Emilie-Fleur, Prévost, Grégoire, Payrastre, Bernard, Manenti, Stéphane
Format: Article
Language:English
Subjects:
Animals
cdc25 Phosphatases - metabolism
Cell Line, Tumor
Cell Proliferation
Humans
Life Sciences
Lymphoma, Large-Cell, Anaplastic - enzymology
Lymphoma, Large-Cell, Anaplastic - pathology
Mice
Oncogene Proteins, Fusion - metabolism
Oncogenes
Phosphatidylinositol 3-Kinases - metabolism
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptor Protein-Tyrosine Kinases
Signal Transduction
Up-Regulation
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Summary:Here, we demonstrate that the expression of the dual specificity phosphatase CDC25A, a key regulator of cell cycle progression, is deregulated in Ba/F3 cells expressing the oncogenic protein NPM/ALK and in human cell lines derived from NPM/ALK-positive anaplastic large cell lymphomas (ALCL). Both transcriptional and post-translational mechanisms account for the constitutive expression of the protein, and the PI3K/Akt pathway is essential for this process. Importantly, pharmacological inhibition of CDC25 dramatically inhibits the proliferation of NPM/ALK-expressing cells, while moderately affecting the proliferation of control Ba/F3 cells. RNA interference-mediated downregulation of CDC25A confirmed that NPM/ALK-expressing cells are highly dependent on this protein for their proliferation. Moreover, similar PI3K/AKt-mediated constitutive expression of CDC25A takes place down-stream of other hematological oncogenes, including BCR/ABL in Chronic Myeloid Leukemia and FLT3-ITD in Acute Myeloid Leukemia. Altogether, our data point to the functional link between hematopoietic oncogenic tyrosine kinases and the G(1) cell cycle regulator CDC25A, and we propose that this protein may be a potential therapeutic target in ALCL and other hematological malignancies.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.8.9.8302