期刊
CELL CYCLE
卷 8, 期 9, 页码 1373-1379出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.8.9.8302
关键词
CDC25A; lymphoma; PI3K; proliferation; oncogene; tyrosine kinase
类别
资金
- Pole de Competitivite Cancer Biosante/Fonds Uniques interministeriels des poles de competitivite, by the Region Midi-Pyrenees,
- Association pour la Recherche sur le Cancer (ARC)
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.
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