title: Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.
abstract: Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo 00016, Italy.
authors.forename: Peggy
authors.initials: P
authors.lastname: Kirstetter
authors.forename: Mikkel B
authors.initials: MB
authors.lastname: Schuster
authors.forename: Oksana
authors.initials: O
authors.lastname: Bereshchenko
authors.forename: Susan
authors.initials: S
authors.lastname: Moore
authors.forename: Heidi
authors.initials: H
authors.lastname: Dvinge
authors.forename: Elke
authors.initials: E
authors.lastname: Kurz
authors.forename: Kim
authors.initials: K
authors.lastname: Theilgaard-Mönch
authors.forename: Robert
authors.initials: R
authors.lastname: Månsson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Pedersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.forename: Evelin
authors.initials: E
authors.lastname: Schrock
authors.forename: Bo T
authors.initials: BT
authors.lastname: Porse
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D018450:Disease Progression; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006098:Granulocytes / Q000166:cytology; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics* / Q000473:pathology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000473:pathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D016177:Macrophage-1 Antigen; D050505:Mutant Proteins; D020033:Protein Isoforms; D019009:Proto-Oncogene Proteins c-kit