TitleC/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia.
Publication TypeJournal Article
Year of Publication2012
AuthorsAlberich-Jorda, Meritxell, Wouters Bas, Balastik Martin, Shapiro-Koss Clara, Zhang Hong, Di Ruscio Annalisa, DiRuscio Annalisa, Radomska Hanna S., Ebralidze Alexander K., Amabile Giovanni, Ye Min, Zhang Junyan, Lowers Irene, Avellino Roberto, Melnick Ari, Figueroa Maria E., Valk Peter J. M., Delwel Ruud, and Tenen Daniel G.
JournalJ Clin Invest
Volume122
Issue12
Pagination4490-504
Date Published2012 Dec
ISSN1558-8238
KeywordsAnimals, Azacitidine, CCAAT-Enhancer-Binding Proteins, Cell Differentiation, Cells, Cultured, Chromatin Immunoprecipitation, Decitabine, DNA Methylation, DNA Modification Methylases, Epigenesis, Genetic, Gene Expression Regulation, Leukemic, Genes, Reporter, Granulocyte Colony-Stimulating Factor, Granulocytes, Humans, Leukemia, Myeloid, Acute, Luciferases, Renilla, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Neutrophils, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Protein Binding, Stem Cells, Up-Regulation
Abstract

<p>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.</p>

DOI10.1172/JCI65102
Alternate JournalJ Clin Invest
PubMed ID23160200
PubMed Central IDPMC3533560
Grant ListR01 CA118316 / CA / NCI NIH HHS / United States
R01 HL056745 / HL / NHLBI NIH HHS / United States
T32 HL007917 / HL / NHLBI NIH HHS / United States
R01 HL56745 / HL / NHLBI NIH HHS / United States