Journal
ONCOGENE
Volume 36, Issue 23, Pages 3346-3356Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.488
Keywords
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Funding
- Dutch Cancer Foundation [KWF KUN 2009-4527, KUN 2011-4937]
- Netherlands Organization for Scientific Research (NWO-VIDI)
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In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to 460 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements. Despite this differential enhancer binding, MLL-AF9 and MLL-AF4 still direct a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34(+) and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs. Oncogene (2017)
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