Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma
Summary: Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471931705X |
| _version_ | 1818154610390466560 |
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| author | Jesus García-López Kirby Wallace Joel H. Otero Rachelle Olsen Yong-dong Wang David Finkelstein Brian L. Gudenas Jerold E. Rehg Paul Northcott Andrew M. Davidoff Kevin W. Freeman |
| author_facet | Jesus García-López Kirby Wallace Joel H. Otero Rachelle Olsen Yong-dong Wang David Finkelstein Brian L. Gudenas Jerold E. Rehg Paul Northcott Andrew M. Davidoff Kevin W. Freeman |
| author_sort | Jesus García-López |
| collection | DOAJ |
| description | Summary: Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate with MYCN amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates MYCN oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In in vitro cell transformation assays, we show that Chd5 loss confers most of the MYCN-independent tumor suppressor effects of 1p36 LOH. In contrast, MYCN-driven tumorigenesis selects for NCCs with Arid1a deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing Arid1a as the MYCN-associated tumor suppressor. Our findings reveal that Arid1a loss collaborates with oncogenic MYCN and better define the tumor suppressor functions of 1p36 LOH in NBL. : Garcia-Lopez et al. present a mouse model of high-risk neuroblastoma that includes 1p36 loss and Mycn overexpression. This study substantiates previous predictions from NBL genetic studies, which proposed that two tumor suppressor regions exist in 1p36. It further demonstrates that Mycn overexpression selects for loss of Arid1a during tumorigenesis. Keywords: chromatin remodelers, 1p36 LOH, ARID1A, CHD5, high-risk neuroblastoma |
| first_indexed | 2024-12-11T14:29:15Z |
| format | Article |
| id | doaj.art-239e06a48f6c4cdb89b1b7a993ab5041 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T14:29:15Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-239e06a48f6c4cdb89b1b7a993ab50412022-12-22T01:02:30ZengElsevierCell Reports2211-12472020-01-01302454464.e5Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in NeuroblastomaJesus García-López0Kirby Wallace1Joel H. Otero2Rachelle Olsen3Yong-dong Wang4David Finkelstein5Brian L. Gudenas6Jerold E. Rehg7Paul Northcott8Andrew M. Davidoff9Kevin W. Freeman10Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA; Corresponding authorDepartment of Surgery, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Genetics, Genomics & Informatics, The University of Tennessee Health Science Center (UTHSC), Memphis, TN 38103, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, UT 84112, USAComputational Biology Department, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAComputational Biology Department, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USAPathology Department, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USADepartment of Surgery, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAGenetics, Genomics & Informatics, The University of Tennessee Health Science Center (UTHSC), Memphis, TN 38103, USA; Corresponding authorSummary: Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate with MYCN amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates MYCN oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In in vitro cell transformation assays, we show that Chd5 loss confers most of the MYCN-independent tumor suppressor effects of 1p36 LOH. In contrast, MYCN-driven tumorigenesis selects for NCCs with Arid1a deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing Arid1a as the MYCN-associated tumor suppressor. Our findings reveal that Arid1a loss collaborates with oncogenic MYCN and better define the tumor suppressor functions of 1p36 LOH in NBL. : Garcia-Lopez et al. present a mouse model of high-risk neuroblastoma that includes 1p36 loss and Mycn overexpression. This study substantiates previous predictions from NBL genetic studies, which proposed that two tumor suppressor regions exist in 1p36. It further demonstrates that Mycn overexpression selects for loss of Arid1a during tumorigenesis. Keywords: chromatin remodelers, 1p36 LOH, ARID1A, CHD5, high-risk neuroblastomahttp://www.sciencedirect.com/science/article/pii/S221112471931705X |
| spellingShingle | Jesus García-López Kirby Wallace Joel H. Otero Rachelle Olsen Yong-dong Wang David Finkelstein Brian L. Gudenas Jerold E. Rehg Paul Northcott Andrew M. Davidoff Kevin W. Freeman Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma Cell Reports |
| title | Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma |
| title_full | Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma |
| title_fullStr | Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma |
| title_full_unstemmed | Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma |
| title_short | Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma |
| title_sort | large 1p36 deletions affecting arid1a locus facilitate mycn driven oncogenesis in neuroblastoma |
| url | http://www.sciencedirect.com/science/article/pii/S221112471931705X |
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