Abstract
SummaryUnderstanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans.
Highlights
Translocations of the mixed-lineage leukemia (MLL) gene produce over 120 different MLL fusion proteins (MLL-FPs) that cause aggressive acute leukemias, the most common one being the MLL-AF4 fusion (Ballabio and Milne, 2012; Meyer et al, 2013)
Recruitment of MLL-FPs to gene targets is thought to be controlled by multiple endocrine neoplasia type 1 (Menin), lens epithelium-derived growth factor (LEDGF), and PAFc interactions as well as CXXC binding to unmethylated CpG (uCpG) (Milne et al, 2010; Muntean et al, 2010; Okuda et al, 2014; Yokoyama and Cleary, 2008; Yokoyama et al, 2005)
MLL-AF4 Binds Exclusively to a Subset of uCpGs Using MLL(N) and AF4(C) chromatin immunoprecipitation sequencing (ChIP-seq) in the human MLL-AF4 SEM cell line (Figure 1C), we identified 4,427 peaks and a gene set of 2,597 unique genes (Table S1)
Summary
Translocations of the mixed-lineage leukemia (MLL) gene produce over 120 different MLL fusion proteins (MLL-FPs) that cause aggressive acute leukemias, the most common one being the MLL-AF4 fusion (Ballabio and Milne, 2012; Meyer et al, 2013). Recruitment of MLL-FPs to gene targets is thought to be controlled by Menin, LEDGF, and PAFc interactions as well as CXXC binding to uCpGs (Milne et al, 2010; Muntean et al, 2010; Okuda et al, 2014; Yokoyama and Cleary, 2008; Yokoyama et al, 2005). Recent data suggest that Menin is unimportant for wild-type MLL (Borkin et al, 2015; Li et al, 2013), whereas LEDGF is required for MLL but not MLL-FP recruitment (Zhu et al, 2016) It still remains an open question exactly how MLL-FPs are recruited to particular gene targets
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