title: CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia.
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.
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.|Hematology Department, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertoli
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Helena
authors.initials: H
authors.lastname: Boutzen
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Laure
authors.initials: L
authors.lastname: David
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.|Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U 1016, Paris, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Larrue
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.|Hematology Laboratory, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Vergez
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Fernandez-Vidal
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Lingli
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U 1016, Paris, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Hospital
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U 1016, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Tamburini
authors.affiliation: Hematology Laboratory, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Demur
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.|Hematology Laboratory, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Saland
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Sarry
authors.affiliation: IPSEN Laboratory, Les Ulis, France.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Galcera
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.|Hematology Laboratory, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mansat-De Mas
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Didier
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Dozier
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.|Hematology Department, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.affiliation: Cancer Research Center of Toulouse, Inserm UMR 1037, CNRS ERL 5294, Université de Toulouse, Oncopole, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Manenti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D059447:Cell Cycle Checkpoints; D016923:Cell Death; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020080:Tandem Repeat Sequences; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C535248:2-(2,5-difluorophenyl)-6-((3-(methyl(3-((2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino)propyl)amino)propyl)amino)-1,3-benzoxazole-4,7-dione; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases
keywords: CDC25A; acute myeloid leukemia; cell cycle; differentiation; proliferation