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

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.
AuthorsAdam 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
JournalHaematologica (Haematologica) Vol. 99 Issue 4 Pg. 697-705 (Apr 2014) ISSN: 1592-8721 [Electronic] Italy
PMID24162792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • CCAAT-Enhancer-Binding Protein-alpha
  • Histone Deacetylase Inhibitors
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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