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• W2592787461 abstract "ENL, identified in a genome-scale loss-of-function screen as a crucial requirement for proliferation of acute leukaemia, is required for leukaemic gene expression, and its YEATS chromatin-reader domain is essential for leukaemic growth. Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene give rise to acute myeloid leukaemia (AML). Here, James Bradner and colleagues perform a genome-scale loss-of-function screen using CRISPR–Cas9 technology in MLL-AF4 AML cells. They find that the ENL gene is critical for cell proliferation and use a chemical genetic strategy of targeted protein degradation to show that loss of ENL suppresses transcriptional activation as well as leukaemic growth. ENL-dependent leukaemic growth depends on its YEATS chromatin reader domain, indicating that competitive antagonists of the YEATS domain could be potential therapeutics for AML. A related paper in this week's issue of Nature from Xiaobing Shi and colleagues provides insights into the function of the ENL YEATS domain in recognizing acetylated histones. Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome1. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control2. Despite recent progress made in targeting chromatin regulators in cancer3, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR–Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease." @default.
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• W2592787461 date "2017-03-01" @default.
• W2592787461 modified "2023-10-18" @default.
• W2592787461 title "Transcription control by the ENL YEATS domain in acute leukaemia" @default.
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• W2592787461 doi "https://doi.org/10.1038/nature21688" @default.
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