title: 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.
authors.affiliation: alberich@img.cas.cz or daniel.tenen@nus.edu.sg.
authors.forename: Adam
authors.initials: A
authors.lastname: Liss
authors.forename: Chia-Huey
authors.initials: CH
authors.lastname: Ooi
authors.forename: Polina
authors.initials: P
authors.lastname: Zjablovskaja
authors.forename: Touati
authors.initials: T
authors.lastname: Benoukraf
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Radomska
authors.forename: Chen
authors.initials: C
authors.lastname: Ju
authors.forename: Mengchu
authors.initials: M
authors.lastname: Wu
authors.forename: Martin
authors.initials: M
authors.lastname: Balastik
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Tomas
authors.initials: T
authors.lastname: Brdicka
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Meritxell
authors.initials: M
authors.lastname: Alberich-Jorda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D022763:CCAAT-Enhancer-Binding Protein-alpha; D056572:Histone Deacetylase Inhibitors