Details

Autor(en) / Beteiligte

• Bertoli, Sarah
• Boutzen, Helena
• David, Laure
• Larrue, Clément
• Vergez, François
• Fernandez-Vidal, Anne
• Yuan, Lingli
• Hospital, Marie-Anne
• Tamburini, Jérôme
• Demur, Cécile
• Delabesse, Eric
• Saland, Estelle
• Sarry, Jean-Emmanuel
• Galcera, Marie-Odile
• Mansat-De Mas, Véronique
• Didier, Christine
• Dozier, Christine
• Récher, Christian
• Manenti, Stéphane

Titel

CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia

Ist Teil von

• Oncotarget, 2015-11, Vol.6 (35), p.38061-38078

Ort / Verlag

United States: Impact journals

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• We investigated cell cycle regulation in acute myeloid leukemia cells expressing the FLT3-ITD mutated tyrosine kinase receptor, an underexplored field in this disease. Upon FLT3 inhibition, CDC25A mRNA and protein were rapidly down-regulated, while levels of other cell cycle proteins remained unchanged. This regulation was dependent on STAT5, arguing for FLT3-ITD-dependent transcriptional regulation of CDC25A. CDC25 inhibitors triggered proliferation arrest and cell death of FLT3-ITD as well as FLT3-ITD/TKD AC-220 resistant cells, but not of FLT3-wt cells. Consistently, RNA interference-mediated knock-down of CDC25A reduced the proliferation of FLT3-ITD cell lines. Finally, the clonogenic capacity of primary FLT3-ITD AML cells was reduced by the CDC25 inhibitor IRC-083864, while FLT3-wt AML and normal CD34+ myeloid cells were unaffected. In good agreement, in a cohort of 100 samples from AML patients with intermediate-risk cytogenetics, high levels of CDC25A mRNA were predictive of higher clonogenic potential in FLT3-ITD+ samples, not in FLT3-wt ones.Importantly, pharmacological inhibition as well as RNA interference-mediated knock-down of CDC25A also induced monocytic differentiation of FLT3-ITD positive cells, as judged by cell surface markers expression, morphological modifications, and C/EBPα phosphorylation. CDC25 inhibition also re-induced monocytic differentiation in primary AML blasts carrying the FLT3-ITD mutation, but not in blasts expressing wild type FLT3. Altogether, these data identify CDC25A as an early cell cycle transducer of FLT3-ITD oncogenic signaling, and as a promising target to inhibit proliferation and re-induce differentiation of FLT3-ITD AML cells.