Transcription control by the ENL YEATS domain in acute leukaemia
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 re...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/112743 https://orcid.org/0000-0003-2782-2509 |
| _version_ | 1826209951156011008 |
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| 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. 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 |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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 |
| author_sort | Erb, Michael A. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T14:36:58Z |
| format | Article |
| id | mit-1721.1/112743 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:36:58Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1127432022-10-01T21:50:19Z Transcription control by the ENL YEATS domain in acute leukaemia 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 Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences McGovern Institute for Brain Research at MIT Sanjana, Neville E Shalem, Ophir Zhang, Feng 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. K. Lubin E. Woods 2017-12-14T14:13:56Z 2017-12-14T14:13:56Z 2017-03 2016-05 2017-12-12T16:08:17Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/112743 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 https://orcid.org/0000-0003-2782-2509 http://dx.doi.org/10.1038/NATURE21688 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | 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 Transcription control by the ENL YEATS domain in acute leukaemia |
| title | Transcription control by the ENL YEATS domain in acute leukaemia |
| title_full | Transcription control by the ENL YEATS domain in acute leukaemia |
| title_fullStr | Transcription control by the ENL YEATS domain in acute leukaemia |
| title_full_unstemmed | Transcription control by the ENL YEATS domain in acute leukaemia |
| title_short | Transcription control by the ENL YEATS domain in acute leukaemia |
| title_sort | transcription control by the enl yeats domain in acute leukaemia |
| url | http://hdl.handle.net/1721.1/112743 https://orcid.org/0000-0003-2782-2509 |
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