Transcription control by the ENL YEATS domain in acute leukaemia
Author(s)Erb, Michael A.; Scott, Thomas G.; Li, Bin E.; Xie, Huafeng; Paulk, Joshiawa; Seo, Hyuk-Soo; Souza, Amanda; Roberts, Justin M.; Dastjerdi, Shiva; Buckley, Dennis L.; Nabet, Behnam; Zeid, Rhamy; Offei-Addo, Nana K.; Dhe-Paganon, Sirano; Orkin, Stuart H.; Winter, Georg E.; Bradner, James E.; Sanjana, Neville E; Shalem, Ophir; Zhang, Feng; ... Show more Show less
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Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, 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.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; McGovern Institute for Brain Research at MIT
Nature Publishing Group
Erb, Michael A. et al. “Transcription Control by the ENL YEATS Domain in Acute Leukaemia.” Nature 543, 7644 (March 2017): 270–274 © 2017 Macmillan Publishers Limited, part of Springer Nature
Author's final manuscript