C/EPB alpha proteins, encoded by the CCAAT-enhancer-binding protein a 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/EPB alpha signature characterized by a set of genes up-regulated upon C/EPB alpha activation. We analyzed expression of the C/EPB alpha 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/EPB alpha dysfunctional subset. Remarkably, a large percentage of samples harboring C/EPB alpha biallelic mutations clustered within this subset. We hypothesize that re-activation of the C/EPB alpha signature in the C/EPB alpha dysfunctional subset could have therapeutic potential. In search for small molecules able to reverse the low expression of the C/EPB alpha signature we applied the connectivity map. This analysis predicted positive connectivity between the C/EPB alpha activation signature and histone deacetylase inhibitors. We showed that these inhibitors reactivate expression of the C/EPB alpha signature and promote granulocytic differentiation of primary samples from the C/EPB alpha dysfunctional subset harboring biallelic C/EPB alpha mutations. Altogether, our study identifies histone deacetylase inhibitors as potential candidates for the treatment of certain leukemias characterized by down-regulation of the C/EPB alpha signature.