c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification
The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer ampli...
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| Format: | Article |
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American Association for Cancer Research (AACR)
2020
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| Online Access: | https://hdl.handle.net/1721.1/124793 |
| _version_ | 1826208265368764416 |
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| author | Abraham, Brian J. Young, Richard A. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Abraham, Brian J. Young, Richard A. |
| author_sort | Abraham, Brian J. |
| collection | MIT |
| description | The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas. SIGNIFICANCE: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. ©2018 |
| first_indexed | 2024-09-23T14:03:07Z |
| format | Article |
| id | mit-1721.1/124793 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:03:07Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1247932022-10-01T18:51:04Z c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification Abraham, Brian J. Young, Richard A. Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas. SIGNIFICANCE: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. ©2018 NIH (grant no. R35-CA210064) NIH (grant no. R01-CA180692) NIH (grant no. P30-CA021765) 2020-04-22T16:09:22Z 2020-04-22T16:09:22Z 2018-03 2019-03-15T12:51:43Z Article http://purl.org/eprint/type/JournalArticle 2159-8274 2159-8290 https://hdl.handle.net/1721.1/124793 Zimmerman, Mark W., et al., "c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification." Cancer discovery 8, 3 (2018): p. 320-35 doi 10.1158/2159-8290.CD-17-0993 ©2018 Author(s) 10.1158/2159-8290.CD-17-0993 Cancer discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Abraham, Brian J. Young, Richard A. c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification |
| title | c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification |
| title_full | c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification |
| title_fullStr | c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification |
| title_full_unstemmed | c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification |
| title_short | c-MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification |
| title_sort | c myc drives a subset of high risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification |
| url | https://hdl.handle.net/1721.1/124793 |
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