Transcription control by the ENL YEATS domain in acute leukaemia

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Recurrent chromosomal translocations producing a chimaericMLLoncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome1. The preferential involvement of chromatin-associated factors asMLLfusion 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 identifyENLas an unrecognized gene that is specifically required for proliferationin vitroandin 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.

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