Depletion of RUNX1/ETO in t(8:21) AML cells leads to genome-wide changes in transcription factor binding

The t(8:21) translocation is present in approximately 15% of all acute myeloid leukemia (AML) cases. This fusion protein is a leukaemia-initiating transcription factor that interferes with RUNX1 function, resulting in a block in differentiation and in the development of AML.

However the molecular details of the mechanism of deregulation are still obscure. It is important to identify RUNX1/ETO target sites at the genome-wide level, to define its individual role in reprogramming gene expression networks. To this end we performed Chip-sequencing and found peaks located in already established RUNX1/ETO target genes as well as in the TERT – CLPTM1L locus.

Since RUNX1 and RUNX1/ETO bind to the same sequence through its RHD domain, it is also important to elucidate how chromatin and RUNX1 occupancy respond to loss of RUNX/ETO binding at its target genes. RUNX1/ETO depletion increased the number of RUNX1 peaks and resulted in an increased number of de novo RUNX1 binding sites. We show that removal of RUNX1/ETO leads to reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding.