Transcription control by the ENL YEATS domain in acute leukemia

Recurrent chromosomal translocations involving the mixed lineage leukemia gene (MLL) give rise to a highly aggressive acute leukemia associated with poor clinical outcome(1). The preferential involvement of chromatin-associated factors in MLL rearrangement belies a dependency on transcription control(2). Despite recent progress made in targeting chromatin regulators in cancer(3), available therapies for this well-characterized disease remain inadequate, prompting the present effort to qualify new targets for therapeutic intervention. Using unbiased, emerging CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in MLL-AF4-positive acute leukemia, we identified ENL (eleven-nineteen leukemia) as an unrecognized dependency particularly indispensable for proliferation in vitro and in vivo. To explain the mechanistic role for ENL in leukemia pathogenesis and dynamic transcription control, we pursued a chemical genetic strategy utilizing targeted protein degradation. Acute ENL loss suppresses transcription initiation and elongation genome-wide, with pronounced effects at genes featuring disproportionate ENL load. Importantly, ENL-dependent leukemic growth was contingent upon an intact YEATS chromatin reader domain. These findings reveal a novel dependency in acute leukemia and a first mechanistic rational for disrupting the YEATS domain in disease.