Abstract
SummaryAcute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML.
Highlights
Acute myeloid leukemia (AML) is the most common acute leukemia in adults
T(3;21) and t(8;21) AML Display Different Epigenetic Landscapes and Gene Expression Profiles In order to obtain a first indication of the similarities and differences in the cistromes regulating gene expression patterns in t(8;21) and t(3;21) AML we mapped the accessible chromatin landscape by identifying all DNase I hypersensitive site (DHS) in purified CD34+ leukemic blast cells of two t(3;21) and two t(8;21) AML patients, two sets of normal CD34+ progenitor cells purified as mobilized peripheral blood stem cells (PBSCs) from peripheral blood, and a t(3;21) cell line derived from a chronic myelogenous leukemia (CML) patient in blast crisis (SKH-1; Mitani et al, 1994))
We performed a bootstrapping analysis, which highlights the significance of occupied motif co-clustering within windows of 50 bp, and plotted enriched motifs in a co-clustering matrix (Figures 3E, 3F, S3F, and S3G). These analyses showed that RUNX1-EVI1binding sites clustered with occupied PU.1/ERG (ETS), AP-1, and GATA motifs, suggesting that they may exist as a complex
Summary
Loke et al compare the regulatory signature of two related types of acute myeloid leukemia, t(8;21) expressing RUNX1-ETO and t(3;21) expressing RUNX1-EVI1. Each fusion protein displays a distinct binding pattern and cooperates with different transcription factors to impact the epigenome, but both downregulate the myeloid differentiation regulator C/EBPa. Highlights d t(8;21) and t(3;21) AML are regulated by unique gene regulatory networks. GSE87286 d RUNX1-ETO and RUNX1-EVI1 have different binding patterns and binding partners d Depletion of each fusion protein initiates C/EBPa-dependent myeloid differentiation d t(8;21) AML survival depends on RUNX1, whereas t(3;21) AML survival requires GATA2. 2017, Cell Reports 19, 1654–1668 May 23, 2017 a 2017 The Author(s).
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