Identification of a Dynamic Core Transcriptional Regulatory Network for t(8;21) AML

Ptasinska, A; Assi, S; Williamson, D; Cauchy, P; Tenen, D; Cockerill, P; Westhead, D; Heidenreich, O; Bonifer, C

doi:10.1016/j.exphem.2013.05.061

Identification of a Dynamic Core Transcriptional Regulatory Network for t(8;21) AML

Lookup NU author(s): Dr Daniel Williamson, Professor Olaf Heidenreich

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Abstract

The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, after the acquisition of additional mutations, the development of acute myeloid leukemia (AML). We have previously determined genome-wide binding sites of RUNX1/ETO and RUNX1. We also measured open chromatin regions, histone acetylation and RNA-Polymerase II binding as well as global gene expression. Our work demonstrates that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming, including alterations in histone modification patterns and RNA-Polymerase II occupancy as well as inhibition of self-renewal and the induction of myeloid differentiation (Ptasinska et al., 2012, Leukemia). To obtain further insights into the transcriptional network defining t(8;21) AML we have now determined the genome-wide binding sites for the transcription factors RUNX1, LMO2, PU.1 and C/EBPalpha before and after the removal of RUNX1/ETO. We demonstrate that depletion of RUNX1/ETO causes a global re-distribution of RUNX1, LMO2, PU.1 and C/EBPalpha binding. Our studies give detailed insights of the extent of how a single aberrant transcription factor reshapes the epigenetic landscape of normal blood cells into a cancer epigenome. Moreover, the detailed analysis of genome wide data from our perturbation experiments identified a t(8;21)-specific core transcriptional network dynamically responding to the presence or absence of RUNX1/ETO and highlights multiple pathways relevant for therapeutic intervention.