title: Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
abstract: We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBPalpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBPalpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBPalpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.
authors.affiliation: EMBL Mouse Biology Unit, Via Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Oxana
authors.initials: O
authors.lastname: Bereshchenko
authors.forename: Elena
authors.initials: E
authors.lastname: Mancini
authors.forename: Susan
authors.initials: S
authors.lastname: Moore
authors.forename: Daniel
authors.initials: D
authors.lastname: Bilbao
authors.forename: Robert
authors.initials: R
authors.lastname: Månsson
authors.forename: Sidinh
authors.initials: S
authors.lastname: Luc
authors.forename: Amit
authors.initials: A
authors.lastname: Grover
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: David
authors.initials: D
authors.lastname: Bryder
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha