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

A Ptasinska, S A Assi, D Mannari, S R James, D Williamson, J Dunne, M Hoogenkamp, M Wu, M Care, H Mcneill, P Cauchy, M Cullen, R M Tooze, D G Tenen, B D Young, P N Cockerill, D R Westhead, O Heidenreich, C Bonifer

Research output: Contribution to journalArticlepeer-review

109 Citations (Scopus)
269 Downloads (Pure)

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, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.
Original languageEnglish
Pages (from-to)1829-1841
JournalLeukemia
Volume26
Issue number8
Early online date16 Mar 2012
DOIs
Publication statusPublished - 1 Aug 2012

Fingerprint

Dive into the research topics of 'Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding'. Together they form a unique fingerprint.

Cite this