title: C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia.
abstract: C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs.
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Alberich-Jordà
authors.forename: Bas
authors.initials: B
authors.lastname: Wouters
authors.forename: Martin
authors.initials: M
authors.lastname: Balastik
authors.forename: Clara
authors.initials: C
authors.lastname: Shapiro-Koss
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Annalisa
authors.initials: A
authors.lastname: Di Ruscio
authors.forename: Annalisa
authors.initials: A
authors.lastname: DiRuscio
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Radomska
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Ebralidze
authors.forename: Giovanni
authors.initials: G
authors.lastname: Amabile
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.forename: Junyan
authors.initials: J
authors.lastname: Zhang
authors.forename: Irene
authors.initials: I
authors.lastname: Lowers
authors.forename: Roberto
authors.initials: R
authors.lastname: Avellino
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D017930:Genes, Reporter; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D006098:Granulocytes; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C405462:CCAAT-enhancer-binding protein-gamma; C515848:CEBPA protein, human; D016179:Granulocyte Colony-Stimulating Factor; D000077209:Decitabine; D049410:Luciferases, Renilla; D015254:DNA Modification Methylases; D001374:Azacitidine