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- Title
C/EBP? deregulation results in differentiation arrest in acute myeloid leukemia.
- Authors
Alberich-Jordà, Meritxell; Wouters, Bas; Balastik, Martin; Shapiro-Koss, Clara; Hong Zhang; DiRuscio, Annalisa; Radomska, Hanna S.; Ebralidze, Alexander K.; Amabile, Giovanni; Ye, Min; Junyan Zhang; Lowers, Irene; Avellino, Roberto; Melnick, Ari; Figueroa, Maria E.; Valk, Peter J.M.; Delwe, Ruud; Tenen, Daniel G.
- Abstract
C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPܓ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPa hypermethylation/silencing. Similarly, C/EBPܓ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPa, as C/EBPa mediates C/EBPܓ 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/EBPa-C/EBPܓ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPܓ mediates the myeloid differentiation arrest induced by C/EBPa deficiency and that targeting the C/EBPa-C/EBPܓ axis rescues neutrophilic differentiation in this unique subset of AMLs.
- Subjects
ACUTE myeloid leukemia; TRANSCRIPTION factors; TISSUES; GENE silencing; HEMATOPOIETIC stem cells; NEUTROPHILS; CELL differentiation
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 12, p1
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI65102