The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs

The t(8;21) acute myeloid leukemia (AML)-associated oncoprotein AML1-ETO disrupts normal hematopoietic differentiation. Here, we have investigated its effects on the transcriptome and epigenome in t(8,21) patient cells. AML1-ETO binding was found at promoter regions of active genes with high levels of histone acetylation but also at distal elements characterized by low acetylation levels and binding of the hematopoietic transcription factors LYL1 and LMO2. In contrast, ERG, FLI1, TAL1, and RUNX1 bind at all AML1-ETO-occupied regulatory regions, including those of the AML1-ETO gene itself, suggesting their involvement in regulating AML1-ETO expression levels. While expression of AML1-ETO in myeloid differentiated induced pluripotent stem cells (iPSCs) induces leukemic characteristics, overexpression increases cell death. We find that expression of wild-type transcription factors RUNX1 and ERG in AML is required to prevent this oncogene overexpression. Together our results show that the interplay of the epigenome and transcription factors prevents apoptosis in t(8;21) AML cells. [Display omitted] •Global analysis of AML1-ETO (AE) in two patient blasts•The AML1-ETO complex consists of hematopoietic, chromatin, and splicing regulators•ERG or RUNX1 knockdown upregulates AML1-ETO expression•AML1-ETO overexpression in differentiated iPSCs induces apoptosis As part of the International Human Epigenome Consortium (IHEC), Mandoli et al. investigate the AML1-ETO-associated epigenome, transcriptome, and proteome in t(8;21) patient cells and cell lines. Together their results suggest that a balanced interplay between the chromatin environment and expression of RUNX1 and ERG prevent AML1-ETO oncogene overdose and thereby inhibit apoptosis. Explore the Cell Press IHEC webportal at www.cell.com/consortium/IHEC.