title: Hypomethylating agents reactivate FOXO3A in acute myeloid leukemia.
abstract: The deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agent, notably azacitidine, constitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine, and to a lesser degree azacitidine, induced the activation of checkpoint kinases Chk-1 and Chk-2 and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box O3, best known as FOXO3A, whose phosphorylation has been related to poor prognosis in AML. The dephoasphorylation of FOXO3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FOXO3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML-derived, azacitidine-sensitive SKM-1S cells upregulated FOXO3A and the pro-apoptotic FOXO3A targets BIM and PUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the reactivation of FOXO3A may contribute to the effects of hypomethylating agents in malignant blasts.
authors.affiliation: INSERM, U848, Villejuif, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Thépot
authors.forename: Elodie
authors.initials: E
authors.lastname: Lainey
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.forename: Marie
authors.initials: M
authors.lastname: Sébert
authors.forename: Carole
authors.initials: C
authors.lastname: Leroy
authors.forename: Lionel
authors.initials: L
authors.lastname: Adès
authors.forename: Maximilien
authors.initials: M
authors.lastname: Tailler
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Fanny
authors.initials: F
authors.lastname: Baran-Marszak
authors.forename: Hervé
authors.initials: H
authors.lastname: Roudot
authors.forename: Virginie
authors.initials: V
authors.lastname: Eclache
authors.forename: Claude
authors.initials: C
authors.lastname: Gardin
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Simone
authors.initials: S
authors.lastname: Boehrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D019175:DNA Methylation; D004260:DNA Repair; D000077209:Decitabine; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C468783:H2AX protein, human; D006657:Histones; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000077209:Decitabine; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D001374:Azacitidine