Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal.
Bottom Line: We show that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind to identical DNA sites in a mutually exclusive fashion.Perturbation of this equilibrium in t(8;21) cells by RUNX1/ETO depletion leads to a global redistribution of transcription factor complexes within preexisting open chromatin, resulting in the formation of a transcriptional network that drives myeloid differentiation.Our work demonstrates on a genome-wide level that the extent of impaired myeloid differentiation in t(8;21) is controlled by the dynamic balance between RUNX1/ETO and RUNX1 activities through the repression of transcription factors that drive differentiation.
Affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.Show MeSH
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Mentions: We next evaluated whether C/EBPα was required for the upregulation of repressed RUNX1/ETO target genes. For this purpose, we depleted RUNX1/ETO with and without a concomitant C/EBPα knockdown. Knockdown of RUNX1/ETO led to a 2-fold increase in C/EBPα expression (Figures 3A, 7A, and 7B) and increases in expression of the direct RUNX1/ETO target genes, including MS4A3, NKG7, and RNASE2, which all show increased C/EBPα binding upon RUNX1/ETO depletion (Figures 7C and 7D; data not shown). Codepletion of C/EBPα diminished the induction of the three target genes in both Kasumi-1 and SKNO-1 cells (Figures 7D and S7B–S7D). These data indicate that derepression of C/EBPα caused by RUNX1/ETO depletion is required for the full upregulation of a number of RUNX1/ETO target genes. However, we cannot rule out a similar function for other C/EBP members and in particular C/EBPδ and C/ EBPε, which are both upregulated upon RUNX1/ETO knockdown (Figure 5B and data not shown). Nevertheless, our data confirm that C/EBPα plays an important role in orchestrating a transcriptional network that drives myeloid differentiation downstream of the original RUNX1/ETO network (Figure 7E).
Affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.