Transcription control by the ENL YEATS domain in acute leukemia

DSpace/Manakin Repository

Transcription control by the ENL YEATS domain in acute leukemia

Citable link to this page

 

 
Title: Transcription control by the ENL YEATS domain in acute leukemia
Author: 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.; Sanjana, Neville E.; Shalem, Ophir; Nabet, Behnam; Zeid, Rhamy; Offei-Addo, Nana K.; Dhe-Paganon, Sirano; Zhang, Feng; Orkin, Stuart H.; Winter, Georg E.; Bradner, James E.

Note: Order does not necessarily reflect citation order of authors.

Citation: Erb, M. A., T. G. Scott, B. E. Li, H. Xie, J. Paulk, H. Seo, A. Souza, et al. 2017. “Transcription control by the ENL YEATS domain in acute leukemia.” Nature 543 (7644): 270-274. doi:10.1038/nature21688. http://dx.doi.org/10.1038/nature21688.
Full Text & Related Files:
Abstract: Recurrent chromosomal translocations involving the mixed lineage leukemia gene (MLL) give rise to a highly aggressive acute leukemia associated with poor clinical outcome1. The preferential involvement of chromatin-associated factors in MLL rearrangement 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 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.
Published Version: doi:10.1038/nature21688
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497220/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34491933
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters