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 1

CEBPG RNA is upregulated in the absence of CEBPA in a subset of human AML and in murine C/EBPα-deficient hematopoietic stem/progenitor cells.

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CEBPG RNA is upregulated in the absence of CEBPA in a subset of human A...
(A) Pairwise correlations between GEPs of 526 AML samples hybridized to the Affymetrix HGU133Plus 2.0 GeneChips identifies a subset with high CEBPG and low C/EBPA levels. The rectangle amplifies a cluster that gathers samples with defects in CEBPA. The bar and histograms next to each sample indicate the following: CEBPA status (mutations are shown in red and silencing in green), CEBPA, and CEBPG expression levels. In total, 8 cases present high CEBPG levels and CEBPA silencing due to hypermethylation. The single case with a blue arrow is a patient without CEBPA mutation but with very high CEBPA mRNA expression levels and without CEBPG mRNA expression. As this case shows a very similar gene expression signature, we propose this represents another defect within the C/EBPα/C/EBPγ “pathway.” (B) Quantitative RT-PCR analysis in murine sorted LKS cells from CebpaFlox/Flox cre– (WT) and CebpaFlox/Flox cre+ (KO) mice. Cebpa and Cebpg mRNA expression levels were determined as percentage of Gapdh (relative expression) and represent the average value plus SD of at least 5 mice in each group. *P = 1.1 × 10–7; **P = 1.6 × 10–6. (C) C/EBPα-KO LKS cells were transduced with either pMSCV empty vector or C/EBPα pMSCV expression construct. Cebpa and Cebpg mRNA expression levels were determined in GFP+ cells 1 days after transduction. Data are the average of 3 independent experiments expressed as percentage of GAPDH plus SD. *P = 0.00045; **P = 0.0065.