TY - JOUR
T1 - The whole-genome landscape of Burkitt lymphoma subtypes
AU - Panea, Razvan I.
AU - Love, Cassandra L.
AU - Shingleton, Jennifer R.
AU - Reddy, Anupama
AU - Bailey, Jeffrey A.
AU - Moormann, Ann M.
AU - Otieno, Juliana A.
AU - Ong’echa, John Michael
AU - Oduor, Cliff I.
AU - Schroeder, Kristin M.S.
AU - Masalu, Nestory
AU - Chao, Nelson J.
AU - Agajanian, Megan
AU - Major, Michael B.
AU - Fedoriw, Yuri
AU - Richards, Kristy L.
AU - Rymkiewicz, Grzegorz
AU - Miles, Rodney R.
AU - Alobeid, Bachir
AU - Bhagat, Govind
AU - Flowers, Christopher R.
AU - Ondrejka, Sarah L.
AU - Hsi, Eric D.
AU - Choi, William W.L.
AU - Au-Yeung, Rex K.H.
AU - Hartmann, Wolfgang
AU - Lenz, Georg
AU - Meyerson, Howard
AU - Lin, Yen Yu
AU - Zhuang, Yuan
AU - Luftig, Micah A.
AU - Waldrop, Alexander
AU - Dave, Tushar
AU - Thakkar, Devang
AU - Sahay, Harshit
AU - Li, Guojie
AU - Palus, Brooke C.
AU - Seshadri, Vidya
AU - Kim, So Young
AU - Gascoyne, Randy D.
AU - Levy, Shawn
AU - Mukhopadyay, Minerva
AU - Dunson, David B.
AU - Dave, Sandeep S.
N1 - Funding Information:
1Center for Genomic and Computational Biology and Department of Medicine, Duke University, Durham, NC;2Department of Pathology and Laboratory Medicine, Brown University, Providence, RI; 3Department of Medicine, University of Massachusetts, Worcester, MA; 4Jaramogi Oginga Odinga Teaching and Referral Hospital, Ministry of Health, Kisumu, Kenya; 5Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya; 6Bugando Medical Center, Mwanza, Tanzania; 7Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO; 8University of North Carolina, Chapel Hill, NC; 9Poland Flow Cytometry Laboratory, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland; 10Department of Pathology, University of Utah, Salt Lake City, UT; 11Department of Pathology and Cell Biology, Columbia University, New York, NY; 12Department of Hematology and Medical Oncology, Emory University, Atlanta, GA; 13Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH; 14Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China; 15The University of Hong Kong, Queen Mary Hospital, Hong Kong, China;16Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany; 17Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany; 18Medical Department A, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany; 19Department of Pathology, Case Western Reserve University, Cleveland, OH; 20Department of Immunology and 21Department of Molecular Genetics and Microbiology, Duke University, Durham, NC; 22Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, BC, Canada; 23HudsonAlpha Institute for Biotechnology, Huntsville, AL; and 24Department of Statistical Science, Duke University, Durham, NC
Funding Information:
Conflict-of-interest disclosure: C.R.F. has served as a consultant for AbbVie, AstraZeneca, Bayer, BeiGene, Celgene (unpaid), Denovo Bio-pharma, Genentech/Roche (unpaid), Gilead, OptumRx, Karyopharm, Pharmacyclics/Janssen, and Spectrum and has received research funding from AbbVie, Acerta, BeiGene, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceuticals, Millennium/Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, and the V Foundation. E.D.H. has received research support from and served on scientific advisory panels for AbbVie, Eli Lilly, Seattle Genetics, and Celgene. G.L. has received honoraria from Bayer, Celgene, Gilead, Hexal, Janssen, and Roche; has participated in a consulting or advisory role for Amgen, Bayer, Bristol-Myers Squibb, Celgene, Gilead, Hexal, Janssen, Morphosys, Novartis, and Roche; has been on a speaker’s bureau for Bayer, Celgene, Gilead, Janssen, and Roche; has received research funding from AstraZeneca, Bayer, Celgene, Gilead, Janssen, and Roche; and has had travel, accommodation, and expenses reimbursed by Bayer, Celgene, Gilead, Hexal, Janssen, and Roche. S.S.D. owns equity in Data Driven Bioscience. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019
Y1 - 2019
N2 - Burkitt 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.
AB - Burkitt 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.
UR - http://www.scopus.com/inward/record.url?scp=85073714296&partnerID=8YFLogxK
U2 - 10.1182/blood.2019001880
DO - 10.1182/blood.2019001880
M3 - Article
C2 - 31558468
AN - SCOPUS:85073714296
SN - 0006-4971
VL - 134
SP - 1598
EP - 1607
JO - Blood
JF - Blood
IS - 19
ER -