Oncotarget

Research Papers:

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

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

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Oncotarget. 2015; 6:38061-38078. https://doi.org/10.18632/oncotarget.5706

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Abstract

Sarah Bertoli1,2, Helena Boutzen1, Laure David1, Clément Larrue1,4, François Vergez1,3, Anne Fernandez-Vidal1, Lingli Yuan1, Marie-Anne Hospital4, Jérôme Tamburini4, Cécile Demur3, Eric Delabesse1,3, Estelle Saland1, Jean-Emmanuel Sarry1, Marie-Odile Galcera5, Véronique Mansat-De Mas1,3, Christine Didier1, Christine Dozier1, Christian Récher1,2, Stéphane Manenti1

1Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France

2Hematology Department, Institut Universitaire du Cancer Toulouse – Oncopole, Toulouse, France

3Hematology Laboratory, Institut Universitaire du Cancer Toulouse – Oncopole, Toulouse, France

4Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U 1016, Paris, France

5IPSEN Laboratory, Les Ulis, France

Correspondence to:

Stéphane Manenti, e-mail: stephane.manenti@inserm.fr

Keywords: cell cycle, acute myeloid leukemia, differentiation, proliferation, CDC25A

Received: May 15, 2015     Accepted: October 06, 2015     Published: October 16, 2015

ABSTRACT

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.


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