title: Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis.
abstract: CCAAT/enhancer-binding protein-α (C/EBPα/CEBPA) is mutated in approximately 8% of acute myeloid leukemia (AML) in both familial and sporadic AML and, with FLT3 and NPM1, has received most attention as a predictive marker of outcome in patients with normal karyotype disease. Mutations clustering to either the N- or C-terminal (N- and C-ter) portions of the protein have different consequences on the protein function. In familial cases, the N-ter form is inherited with patients exhibiting long latency period before the onset of overt disease, typically with the acquisition of a C-ter mutation. Despite the essential insights murine models provide the functional consequences of wild-type C/EBPα in human hematopoiesis and how different mutations are involved in AML development have received less attention. Our data underline the critical role of C/EBPα in human hematopoiesis and demonstrate that C/EBPα mutations (alone or in combination) are insufficient to convert normal human hematopoietic stem/progenitor cells into leukemic-initiating cells, although individually each altered normal hematopoiesis. It provides the first insight into the effects of N- and C-ter mutations acting alone and to the combined effects of N/C double mutants. Our results mimicked closely what happens in CEBPA mutated patients.
authors.affiliation: Haematopoietic Stem Cell Laboratory, Cancer Research UK, London, UK.
authors.forename: O
authors.initials: O
authors.lastname: Quintana-Bustamante
authors.forename: S
authors.initials: S
authors.lastname: Lan-Lan Smith
authors.forename: E
authors.initials: E
authors.lastname: Griessinger
authors.forename: Y
authors.initials: Y
authors.lastname: Reyal
authors.forename: J
authors.initials: J
authors.lastname: Vargaftig
authors.forename: T A
authors.initials: TA
authors.lastname: Lister
authors.forename: J
authors.initials: J
authors.lastname: Fitzgibbon
authors.forename: D
authors.initials: D
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002453:Cell Cycle; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D000090243:Nucleophosmin; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001613:beta 2-Microglobulin / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D012333:RNA, Messenger; D001613:beta 2-Microglobulin; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3