title: C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo.
abstract: CCAAT enhancer binding protein-alpha (C/EBPalpha) inhibits proliferation in multiple cell types; therefore, we evaluated whether C/EBPalpha-deficient hematopoietic progenitor cells (HPCs) have an increased proliferative potential in vitro and in vivo. In this study we demonstrate that C/EBPalpha(-/-) fetal liver (FL) progenitors are hyperproliferative, show decreased differentiation potential, and show increased self-renewal capacity in response to hematopoietic growth factors (HGFs). There are fewer committed bipotential progenitors in C/EBPalpha(-/-) FL, whereas multipotential progenitors are unaffected. HGF-dependent progenitor cell lines can be derived by directly culturing C/EBPalpha(-/-) FL cells in vitro Hyperproliferative spleen colonies and myelodysplastic syndrome (MDS) are observed in mice reconstituted with C/EBPalpha(-/-) FL cells, indicating progenitor hyperproliferation in vitro and in vivo. C/EBPalpha(-/-) FL lacked macrophage progenitors in vitro and had impaired ability to generate macrophages in vivo. These findings show that C/EBPalpha deficiency results in hyperproliferation of HPCs and a block in the ability of multipotential progenitors to differentiate into bipotential granulocyte/macrophage progenitors and their progeny.
authors.affiliation: Laboratory of Protein Dynamics and Signaling, Science Applications International Corporation-Frederick, Inc, Frederick, MD 20702-1201, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Heath
authors.forename: Hyung Chan
authors.initials: HC
authors.lastname: Suh
authors.forename: Matthew
authors.initials: M
authors.lastname: Holman
authors.forename: Katie
authors.initials: K
authors.lastname: Renn
authors.forename: John M
authors.initials: JM
authors.lastname: Gooya
authors.forename: Sarah
authors.initials: S
authors.lastname: Parkin
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Klarmann
authors.forename: Mariaestela
authors.initials: M
authors.lastname: Ortiz
authors.forename: Peter
authors.initials: P
authors.lastname: Johnson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Keller
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D017690:Cell Transplantation; D002478:Cells, Cultured; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D007377:Interleukin-3; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met