title: Targeting CHK1 inhibits cell proliferation in FLT3-ITD positive acute myeloid leukemia.
abstract: CHK1 Ser/Thr kinase, a well characterized regulator of DNA damage response, is also involved in normal cell cycle progression. In this study, we investigate how CHK1 participates to proliferation of acute myeloid leukemia cells expressing the mutated FLT3-ITD tyrosine kinase receptor. Pharmacological inhibition of CHK1 as well as its shRNA mediated down regulation reduced the proliferation rate of FLT-ITD expressing leukemic cell lines in a cytostatic manner. Flow cytometry analysis revealed no accumulation in a specific phase of the cell cycle upon CHK1 inhibition. Accordingly, lentiviral-mediated CHK1 overexpression increased the proliferation rate of FLT3-ITD expressing cells, as judged by cell viability and [3H] thymidine incorporation experiments. By contrast, expression of a ser280 mutant did not, suggesting that phosphorylation of this residue is an important determinant of CHK1 proliferative function. Clonogenic growth of primary leukemic cells from patients in semi-solid medium was reduced upon CHK1 inhibition, confirming the data obtained with leukemic established cell lines. Surprisingly, 3 out of 4 CHK1 inhibitory compounds tested in this study were also potent inhibitors of the FLT3-ITD tyrosine kinase receptor. Altogether, these data identify CHK1 as a regulator of FLT3-ITD-positive leukemic cells proliferation, and they open interesting perspectives in terms of new therapeutic strategies for these pathologies.
authors.affiliation: Cancer Research Center of Toulouse, Inserm Unité Mixte de Recherche 1037, CNRS Equipe de Recherche labellisée 5294, Université de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, France; Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
authors.forename: Ling Li
authors.initials: LL
authors.lastname: Yuan
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U 1016, Paris, France.
authors.forename: Alexa
authors.initials: A
authors.lastname: Green
authors.affiliation: Cancer Research Center of Toulouse, Inserm Unité Mixte de Recherche 1037, CNRS Equipe de Recherche labellisée 5294, Université de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors.forename: Laure
authors.initials: L
authors.lastname: David
authors.affiliation: Cancer Research Center of Toulouse, Inserm Unité Mixte de Recherche 1037, CNRS Equipe de Recherche labellisée 5294, Université de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Dozier
authors.affiliation: Cancer Research Center of Toulouse, Inserm Unité Mixte de Recherche 1037, CNRS Equipe de Recherche labellisée 5294, Université de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, France; Service d'Hématologie, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.affiliation: Cancer Research Center of Toulouse, Inserm Unité Mixte de Recherche 1037, CNRS Equipe de Recherche labellisée 5294, Université de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Didier
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: Cancer Research Center of Toulouse, Inserm Unité Mixte de Recherche 1037, CNRS Equipe de Recherche labellisée 5294, Université de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, France. Electronic address: stephane.manenti@inserm.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Manenti
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D017931:DNA Primers; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D017931:DNA Primers; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: Acute myeloid leukemia; CHK1; Cell cycle; Cell signaling; FLT3-ITD; Proliferation