Abstract
Mixed lineage leukemia protein-1 (MLL1) has a critical role in human MLL1 rearranged leukemia (MLLr) and is a validated therapeutic target. However, its role in regulating global gene expression in MLLr cells, as well as its interplay with MLL1 fusion proteins remains unclear. Here we show that despite shared DNA-binding and cofactor interacting domains at the N terminus, MLL1 and MLL-AF9 are recruited to distinct chromatin regions and have divergent functions in regulating the leukemic transcription program. We demonstrate that MLL1, probably through C-terminal interaction with WDR5, is recruited to regulatory enhancers that are enriched for binding sites of E-twenty-six (ETS) family transcription factors, whereas MLL-AF9 binds to chromatin regions that have no H3K4me1 enrichment. Transcriptome-wide changes induced by different small molecule inhibitors also highlight the distinct functions of MLL1 and MLL-AF9. Taken together, our studies provide novel insights on how MLL1 and MLL fusion proteins contribute to leukemic gene expression, which have implications for developing effective therapies in the future.
Highlights
Histone H3 lysine 4 (H3K4) methyltransferase mixed lineage leukemia protein-1 (MLL1, called MLL, KMT2A, HRX, HTRX and ALL1) is important for epigenetic maintenance of Hox gene expression, and is required for normal fetal and adult hematopoiesis [1]
We show that despite shared DNA-binding as well as cofactor-interacting domains at the N terminus, wild-type MLL1 and MLL-AF9 are recruited to distinct chromatin regions, and have divergent functions in regulating the leukemia transcription program
We further demonstrate that MLL1, partly through its C-terminal interactions with the MLL1 core complex, is mostly recruited to regulatory enhancers that are enriched for H3K4me
Summary
Histone H3 lysine 4 (H3K4) methyltransferase mixed lineage leukemia protein-1 (MLL1, called MLL, KMT2A, HRX, HTRX and ALL1) is important for epigenetic maintenance of Hox gene expression, and is required for normal fetal and adult hematopoiesis [1]. Majority of MLL1 abnormalities involve balanced chromosomal translocations that lead to production of over 70 in-frame oncogenic fusion proteins [3]. MLL1 fusion genes are gain-of-function mutations, recent studies show that wild-type MLL1 allele is still present in vast majority of MLLr leukemia [1]. As wild-type MLL1 and MLL1 fusion proteins share N-terminal DNA-binding domains, it is generally assumed that MLL1 and MLL1 fusion proteins cooperatively regulate a common set of downstream targets [26]. Consistent with this view, direct binding of MLL1 and MLL1 fusion proteins are detected at Hoxa9 [27]. The joint targets of MLL1 and MLL1 fusion proteins has not been extensively characterized in MLLr leukemia beyond a handful of genes and it remains unclear how MLL1 and MLL1 fusion proteins contribute to their gene expression
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