The gene signature in CCAAT-enhancer-binding protein α dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors
Adam 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
Affiliations
Adam Liss
Cancer Science Institute, National University of Singapore, Singapore;University of Michigan, Ann Arbor, MI, USA
Chia-Huey Ooi
Cancer Science Institute, National University of Singapore, Singapore
Polina Zjablovskaja
Institute of Molecular Genetics of the ASCR, Prague, Czech Republic
Touati Benoukraf
Cancer Science Institute, National University of Singapore, Singapore
Hanna S. Radomska
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
Chen Ju
Cancer Science Institute, National University of Singapore, Singapore
Mengchu Wu
Cancer Science Institute, National University of Singapore, Singapore
Martin Balastik
Institute of Molecular Genetics of the ASCR, Prague, Czech Republic
Ruud Delwel
Erasmus University Medical Center, Rotterdam, the Netherlands
Tomas Brdicka
Institute of Molecular Genetics of the ASCR, Prague, Czech Republic
Patrick Tan
Cancer Science Institute, National University of Singapore, Singapore;Cancer and Stem Cell Biology Program, Duke–National University of Singapore (NUS) Graduate Medical School;Genome Institute of Singapore, Singapore
Daniel G. Tenen
Cancer Science Institute, National University of Singapore, Singapore;Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
Meritxell Alberich-Jorda
Institute of Molecular Genetics of the ASCR, Prague, Czech Republic;Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
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.
