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

0435104 - ÚMG 2015 RIV IT eng J - Journal Article
Liss, A. - Ooi, C. - Zjablovskaja, Polina - Benoukraf, T. - Radomska, H.S. - Ju, C. - Wu, M.C. - Balaštík, Martin - Delwel, R. - Brdička, Tomáš - Tan, P. - Tenen, D.G. - Alberich-Jorda, Meritxell
The gene signature in CCAAT-enhancer-binding protein alpha dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors.
Haematologica-The Hematology Journal. Roč. 99, č. 4 (2014), s. 697-705. ISSN 0390-6078
R&D Projects: GA MŠMT LK21307; GA MŠMT(CZ) LK11213
Grant - others:NIH(US) CA66996; NIH(US) CA118316
Institutional support: RVO:68378050
Keywords : C/EBPa * histone deacetylase inhibitor * acute myeloid leukemia
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 5.814, year: 2014

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.
Permanent Link: http://hdl.handle.net/11104/0239070