Expression of RUNX1-ETO Rapidly Alters the Chromatin Landscape and Growth of Early Human Myeloid Precursor Cells

• Main Authors: Monica Nafria, Peter Keane, Elizabeth S. Ng, Edouard G. Stanley, Andrew G. Elefanty, Constanze Bonifer
• Format: Article
• Language: English
• Published: Elsevier 2020-05-01
• Series: Cell Reports
• Subjects: Acute Myeloid Leukemia (AML); RUNX1-ETO; chromatin; human ES cell differentiation; myelopoiesis; single cell RNA-Seq
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720306446

Summary: Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by recurrent mutations in genes encoding transcriptional, chromatin, and/or signaling regulators. The t(8;21) translocation generates the aberrant transcription factor RUNX1-ETO (RUNX1-RUNX1T1), which by itself is insufficient to cause disease. t(8;21) AML patients show extensive chromatin reprogramming and have acquired additional mutations. Therefore, the genomic and developmental effects directly and solely attributable to RUNX1-ETO expression are unclear. To address this, we employ a human embryonic stem cell differentiation system capable of forming definitive 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 early myeloid progenitors, but not of other progenitor types, indicating that oncoprotein-mediated transcriptional reprogramming is highly target cell specific.