Long-range enhancer activity determines <i>Myc</i> sensitivity to Notch inhibitors in T cell leukemia
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- Yumi Yashiro-Ohtani
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and
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- Hongfang Wang
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
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- Chongzhi Zang
- Departments of cBiostatistics and Computational Biology and
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- Kelly L. Arnett
- Department of Biological Chemistry and Molecular Pharmacology,
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- Will Bailis
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and
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- Yugong Ho
- Department of Genetics, and
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- Birgit Knoechel
- Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115;
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- Claudia Lanauze
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and
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- Lumena Louis
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and
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- Katherine S. Forsyth
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and
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- Sujun Chen
- Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China 200092
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- Yoonjie Chung
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and
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- Jonathan Schug
- Department of Genetics, and
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- Gerd A. Blobel
- Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104;
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- Stephen A. Liebhaber
- Department of Genetics, and
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- Bradley E. Bernstein
- Broad Institute and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115;
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- Stephen C. Blacklow
- Department of Biological Chemistry and Molecular Pharmacology,
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- Xiaole Shirley Liu
- Departments of cBiostatistics and Computational Biology and
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- Jon C. Aster
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
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- Warren S. Pear
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and
説明
<jats:title>Significance</jats:title> <jats:p> The protooncogene c-Myc (Myc) is an oncogenic driver in many cancers, but is difficult to target directly with drugs. An alternative strategy is to use drugs that inhibit factors that regulate <jats:italic>Myc</jats:italic> expression. Notch drives <jats:italic>Myc</jats:italic> expression in most T-cell leukemias, but clinical trials of Notch inhibitors have been disappointing, possibly because cells emerge that express <jats:italic>Myc</jats:italic> in a Notch-independent fashion. Here we identify the genomic switches that regulate <jats:italic>Myc</jats:italic> expression in the Notch-inhibitor–sensitive and –resistant states. Our findings suggest that Notch inhibitor resistance occurs through a “switch swap” that relieves Notch dependency while increasing dependency on a different factor, bromodomain containing 4 (Brd4). These studies provide a rationale for targeting <jats:italic>Myc</jats:italic> in T cell leukemias with combinations of Notch and Brd4 inhibitors. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 111 (46), E4946-, 2014-11-04
Proceedings of the National Academy of Sciences
