2. Academic Validation
  3. Transcription control by the ENL YEATS domain in acute leukaemia

Transcription control by the ENL YEATS domain in acute leukaemia

  • Nature. 2017 Mar 9;543(7644):270-274. doi: 10.1038/nature21688.
Michael A Erb 1,  Thomas G Scott 1,  Bin E Li 2 3 4,  Huafeng Xie 2 3 4,  Joshiawa Paulk 1,  Hyuk-Soo Seo 5,  Amanda Souza 1,  Justin M Roberts 1,  Shiva Dastjerdi 1,  Dennis L Buckley 1,  Neville E Sanjana 6 7,  Ophir Shalem 6 7,  Behnam Nabet 1,  Rhamy Zeid 1,  Nana K Offei-Addo 5,  Sirano Dhe-Paganon 5,  Feng Zhang 6 7,  Stuart H Orkin 2 3 4 8,  Georg E Winter 1,  James E Bradner 1 9
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  • 2 Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  • 4 Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  • 6 Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
  • 7 McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  • 8 Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 9 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
PMID: 28241139 DOI: 10.1038/nature21688
Abstract

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.

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