期刊
CELL REPORTS
卷 31, 期 8, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.107691
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资金
- U21 Melbourne studentship
- Wellcome Trust Institutional Strategic Support Fund (ISSF)
- Birmingham Cancer Research UK (CRUK) Centre
- University of Melbourne Faculty of Medicine, Dentistry and Health Sciences
- National Health and Medical Research Council of Australia [GNT1068866, GNT1129861, GNT1138717]
- Australian Research Council Special Research Initiative in Stem Cells (Stem Cells Australia)
- Children's Cancer Foundation
- Stafford Fox Medical Research Foundation
- Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme
- Victorian government's Operational Infrastructure Support Program
- MRC [MR/S021469/1] Funding Source: UKRI
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.
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