As part of the International Human Epigenome Consortium (IHEC), Joost Martens, theme Cancer development and immune defense and colleagues 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. They have published their findings in the journal Cell Reports.
The t(8;21) acute myeloid leukemia (AML)-associated oncoprotein AML1-ETO disrupts normal hematopoietic differentiation. They 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. They find that expression of wild-type transcription factors RUNX1 and ERG in AML is required to prevent this oncogene overexpression. Together these results show that the interplay of the epigenome and transcription factors prevents apoptosis in t(8;21) AML cells.
The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs. Amit Mandoli et al, Cell reports, 2016
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