C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

Meritxell Alberich-Jordà, Bas Wouters, Martin Balastik, Clara Shapiro-Koss, Hong Zhang, Annalisa DiRuscio, Hanna S. Radomska, Alexander K. Ebralidze, Giovanni Amabile, Min Ye, Junyan Zhang, Irene Lowers, Roberto Avellino, Ari Melnick, Maria E. Figueroa, Peter J.M. Valk, Ruud Delwel, Daniel G. Tenen

Research output: Contribution to journalArticle

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4490-4504
Number of pages15
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
StatePublished - Dec 3 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Alberich-Jordà, M., Wouters, B., Balastik, M., Shapiro-Koss, C., Zhang, H., DiRuscio, A., Radomska, H. S., Ebralidze, A. K., Amabile, G., Ye, M., Zhang, J., Lowers, I., Avellino, R., Melnick, A., Figueroa, M. E., Valk, P. J. M., Delwel, R., & Tenen, D. G. (2012). C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia. Journal of Clinical Investigation, 122(12), 4490-4504. https://doi.org/10.1172/JCI65102