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 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.
Fernandez-Vidal
Anne
A
INSERM U563-IFR30, Centre de Physiopathologie de Toulouse-Purpan, Département Oncogenèse, signalisation et innovation thérapeutique, Université Paul Sabatier, Toulouse, France.
Mazars
Anne
A
Gautier
Emilie-Fleur
EF
Prévost
Grégoire
G
Payrastre
Bernard
B
Manenti
Stéphane
S
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000378:metabolism*
D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases