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

Nafria, M.; Keane, P.; Ng, E.; Stanley, E. G.; Elefanty, A. G.; Bonifer, C.

doi:10.1101/748921

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bioRxiv · 10.1101/748921

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

Nafria, M.·Keane, P.·Ng, E.·Stanley, E. G.·Elefanty, A. G.·Bonifer, C.

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Abstract

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.

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Nafria, M., Keane, P., Ng, E., Stanley, E. G., Elefanty, A. G., Bonifer, C.. 2019-08-28. 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. https://doi.org/10.1101/748921

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