PT  - JOURNAL ARTICLE
AU  - Monica Nafria
AU  - Peter Keane
AU  - Elizabeth S. Ng
AU  - Edouard G. Stanley
AU  - Andrew G. Elefanty
AU  - Constanze Bonifer
TI  - RUNX1-ETO induction rapidly alters chromatin landscape and growth of a specific sub-population of hESC-derived myeloid precursor cells by interfering with RUNX1 regulation
AID  - 10.1101/748921
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 748921
4099  - http://biorxiv.org/content/early/2019/08/28/748921.short
4100  - http://biorxiv.org/content/early/2019/08/28/748921.full
AB  - Acute myeloid leukemia is a hematopoietic malignancy caused by recurrent mutations in genes encoding transcriptional, epigenetic and/or signaling regulators. The t(8;21) translocation generates the aberrant transcription factor RUNX1-ETO whose expression can be detected in utero but is insufficient to cause overt disease. Although patients harboring cells with the t(8;21) translocation have acquired additional mutations and show extensive epigenetic reprogramming, the effects directly attributable to RUNX1-ETO expression are unclear. To address this question, we used a human embryonic stem cell differentiation system capable of forming definitive human myeloid progenitor cells to express RUNX1-ETO in an inducible fashion. Induction of RUNX1-ETO causes extensive chromatin reprogramming by interfering with RUNX1 binding, blocks differentiation and arrests cellular growth, whereby growth arrest is reversible following RUNX1-ETO removal. Single cell gene expression analyses show that RUNX1-ETO induction alters the differentiation of a defined sub-population of progenitors, indicating that oncoprotein-mediated transcriptional reprogramming is highly target cell specific.