C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia
Meritxell Alberich-Jordà, … , Ruud Delwel, Daniel G. Tenen
Meritxell Alberich-Jordà, … , Ruud Delwel, Daniel G. Tenen
Published November 19, 2012
Citation Information: J Clin Invest. 2012;122(12):4490-4504. https://doi.org/10.1172/JCI65102.
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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

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

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Figure 7

DAC treatment restores the C/EBPα-C/EBPγ balance and promotes differentiation of primary human AML samples characterized by C/EBPα silencing and C/EBPγ upregulation in vitro.

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DAC treatment restores the C/EBPα-C/EBPγ balance and promotes differenti...
(A) Quantitative RT-PCR in 3 independent AML patient samples treated with either mock control or 1 μM DAC. CEBPA and CEBPG expression are shown relative to 18S expression. The y axis indicates fold change as compared with mock treatment. (B) DAC treatment promotes expression of myeloid differentiation markers in AML patient samples. Quantitative RT-PCR in 2 AML patient samples treated with either mock control or 1 μM DAC. The y axis indicates relative expression of G-CSF–R (CSF3R), gelatinase A (MMP2), CEBPE, and neutrophil elastase (ELANE), calculated as relative to GAPDH expression. (C) C/EBPα silenced patient samples treated with DAC or mock control, and analyzed by flow cytometry. Histograms represent expression of CD15 and CD11b after 8 days of treatment (except those indicated by asterisk, which were analyzed after 6 days). Numbers indicate percentage of positive cells.