Abstract |
C/EPBα proteins, encoded by the CCAAT-enhancer-binding protein α gene, play a crucial role in granulocytic development, and defects in this transcription factor have been reported in acute myeloid leukemia. Here, we defined the C/EBPα signature characterized by a set of genes up-regulated upon C/EBPα activation. We analyzed expression of the C/EBPα signature in a cohort of 525 patients with acute myeloid leukemia and identified a subset characterized by low expression of this signature. We referred to this group of patients as the C/EBPα dysfunctional subset. Remarkably, a large percentage of samples harboring C/EBPα biallelic mutations clustered within this subset. We hypothesize that re-activation of the C/EBPα signature in the C/EBPα dysfunctional subset could have therapeutic potential. In search for small molecules able to reverse the low expression of the C/EBPα signature we applied the connectivity map. This analysis predicted positive connectivity between the C/EBPα activation signature and histone deacetylase inhibitors. We showed that these inhibitors reactivate expression of the C/EBPα signature and promote granulocytic differentiation of primary samples from the C/EBPα dysfunctional subset harboring biallelic C/EBPα mutations. Altogether, our study identifies histone deacetylase inhibitors as potential candidates for the treatment of certain leukemias characterized by down-regulation of the C/EBPα signature.
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Authors | Adam Liss, Chia-Huey Ooi, Polina Zjablovskaja, Touati Benoukraf, Hanna S Radomska, Chen Ju, Mengchu Wu, Martin Balastik, Ruud Delwel, Tomas Brdicka, Patrick Tan, Daniel G Tenen, Meritxell Alberich-Jorda |
Journal | Haematologica
(Haematologica)
Vol. 99
Issue 4
Pg. 697-705
(Apr 2014)
ISSN: 1592-8721 [Electronic] Italy |
PMID | 24162792
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- CCAAT-Enhancer-Binding Protein-alpha
- Histone Deacetylase Inhibitors
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Topics |
- Antineoplastic Agents
(pharmacology)
- CCAAT-Enhancer-Binding Protein-alpha
(genetics, metabolism)
- Cell Differentiation
- Cell Line, Tumor
- Cluster Analysis
- Gene Expression Profiling
- Gene Expression Regulation, Leukemic
(drug effects)
- Histone Deacetylase Inhibitors
(pharmacology)
- Humans
- Leukemia, Myeloid, Acute
(genetics, metabolism)
- Mutation
(drug effects, genetics)
- Transcriptional Activation
- Transcriptome
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