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Article: The whole-genome landscape of Burkitt lymphoma subtypes

TitleThe whole-genome landscape of Burkitt lymphoma subtypes
Authors
Keywordsburkitt's lymphoma
crispr
genes
genetics
genome
Issue Date2019
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2019, v. 134 n. 19, p. 1598-1607 How to Cite?
AbstractBurkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry–based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.
Persistent Identifierhttp://hdl.handle.net/10722/281817
ISSN
2017 Impact Factor: 15.132
2015 SCImago Journal Rankings: 6.395
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorPanea, RI-
dc.contributor.authorLove, CL-
dc.contributor.authorShingleton, JR-
dc.contributor.authorReddy, A-
dc.contributor.authorBailey, JA-
dc.contributor.authorMoormann, AM-
dc.contributor.authorOtieno, JA-
dc.contributor.authorOng’echa, JM-
dc.contributor.authorOduor, CI-
dc.contributor.authorSchroeder, KMS-
dc.contributor.authorMasalu, N-
dc.contributor.authorChao, NJ-
dc.contributor.authorAgajanian, M-
dc.contributor.authorMajor, MB-
dc.contributor.authorFedoriw, Y-
dc.contributor.authorRichards, KL-
dc.contributor.authorRymkiewicz, G-
dc.contributor.authorMiles, RR-
dc.contributor.authorAlobeid, B-
dc.contributor.authorBhagat, G-
dc.contributor.authorFlowers, CR-
dc.contributor.authorOndrejka, SL-
dc.contributor.authorHsi, ED-
dc.contributor.authorChoi, WWL-
dc.contributor.authorAu Yeung, RKH-
dc.contributor.authorHartmann, W-
dc.contributor.authorLenz, G-
dc.contributor.authorMeyerson, H-
dc.contributor.authorLin, Y-Y-
dc.contributor.authorZhuang, Y-
dc.contributor.authorLuftig, MA-
dc.contributor.authorWaldrop, A-
dc.contributor.authorDave, T-
dc.contributor.authorThakkar, D-
dc.contributor.authorSahay, H-
dc.contributor.authorLi, G-
dc.contributor.authorPalus, BC-
dc.contributor.authorSeshadri, V-
dc.contributor.authorKim, SY-
dc.contributor.authorGascoyne, RD-
dc.contributor.authorLevy, S-
dc.contributor.authorMukhopadyay, M-
dc.contributor.authorDunson, DB-
dc.contributor.authorDave, SS-
dc.date.accessioned2020-03-27T04:22:52Z-
dc.date.available2020-03-27T04:22:52Z-
dc.date.issued2019-
dc.identifier.citationBlood, 2019, v. 134 n. 19, p. 1598-1607-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/281817-
dc.description.abstractBurkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry–based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.rightsThis research was originally published in [Journal Title]. Author(s). Title. [Journal Title]. Year;Vol,Issue:pp-pp. © the American Society of Hematology.-
dc.subjectburkitt's lymphoma-
dc.subjectcrispr-
dc.subjectgenes-
dc.subjectgenetics-
dc.subjectgenome-
dc.titleThe whole-genome landscape of Burkitt lymphoma subtypes-
dc.typeArticle-
dc.identifier.emailChoi, WWL: choiwl@hku.hk-
dc.identifier.emailAu Yeung, RKH: rex.auyeung@hku.hk-
dc.identifier.authorityChoi, WWL=rp00247-
dc.identifier.authorityAu Yeung, RKH=rp01877-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1182/blood.2019001880-
dc.identifier.pmid31558468-
dc.identifier.pmcidPMC6871305-
dc.identifier.scopuseid_2-s2.0-85073714296-
dc.identifier.hkuros309560-
dc.identifier.volume134-
dc.identifier.issue19-
dc.identifier.spage1598-
dc.identifier.epage1607-
dc.publisher.placeUnited States-

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