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24162792
The gene signature in CCAAT-enhancer-binding protein α dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors.

Haematologica, 2014/4;99(4):697-705.

Liss A[1], Ooi CH, Zjablovskaja P, Benoukraf T, Radomska HS, Ju C, Wu M, Balastik M, Delwel R, Brdicka T, Tan P, Tenen DG, Alberich-Jorda M

Affiliations

PMID: 24162792DOI: 10.3324/haematol.2013.093278

Impact factor: 11.047

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.
MeSH terms
Antineoplastic Agents; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Cell Line, Tumor; Cluster Analysis; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Histone Deacetylase Inhibitors; Humans; Leukemia, Myeloid, Acute; Mutation; Transcriptional Activation; Transcriptome
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