ArticleNature genetics2022
Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation.
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Article in Nature genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43citing papers in PubMed
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43 citing papers in PubMed, 73 citations in OpenAlex.
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Authors and funding
26 authors at 8 institutions in 2 countries.
Hongbo Yang *Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
Hui Zhang *Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Yu Luan *Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.ORCID http://orcid.org/0000-0003-1778-9071
Tingting LiuDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
Wentao YangDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Kathryn G RobertsDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0001-7626-4043
Mao-Xiang QianDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Bo ZhangBioinformatics and Genomics Program, The Pennsylvania State University, University Park, PA, USA.
Wenjian YangDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-7305-5649
Virginia Perez-AndreuDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Jie XuDepartment of Biochemistry and Molecular Biology, Penn State School of Medicine, Hershey, PA, USA.
Sriranga IyyankiDepartment of Biochemistry and Molecular Biology, Penn State School of Medicine, Hershey, PA, USA.
Da KuangDepartment of Computer and Information Science, University of Pennsylvania, Philadelphia, PA, USA.
Lena A StasiakDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.
Shalini C ReshmiDepartment of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Julie Gastier-FosterDepartment of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Colton SmithDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Ching-Hon PuiDepartment of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0003-0303-5658
William E EvansDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-9333-5322
Stephen P HungerDivision of Oncology and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-5492-3957
Leonidas C PlataniasRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
Mary V RellingDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-3720-9591
Charles G MullighanDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-1871-1850
Mignon L LohDepartment of Pediatrics, Benioff Children's Hospital and the Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Feng YueDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA. yue@northwestern.edu.ORCID http://orcid.org/0000-0002-7954-5462
Jun J YangDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. jun.yang@stjude.org.ORCID http://orcid.org/0000-0002-0770-9659
St. Jude Children's Research Hospital · USNorthwestern University · USNationwide Children's Hospital · USPenn State Milton S. Hershey Medical Center · USChildren's Hospital of Philadelphia · USPennsylvania State University · USUniversity of California, San Francisco · USUniversity of Pennsylvania · US
Funding
NCTN BIQSFP ANBL1531 (NRT)U10CA180886 · NCI · PUBLIC HEALTH INSTITUTE · PI Douglas S. Hawkins · 2014 to 2026
$390.6MCOG FOREIGN ACCRUALU10CA098543 · NCI · NATIONAL CHILDHOOD CANCER FOUNDATION · PI ADAMSON, PETER C. · 2003 to 2013
$335.5MViral Vector Technology (VVTSR)P30CA021765 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI CHARLES ROBERTS · 1985 to 2026
$166.9MCOG SDMC - Statistics CoreU10CA180899 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI TODD A ALONZO · 2014 to 2026
$132.8MChildren's Oncology Group Statistics &Data Center GrantU10CA098413 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI DEVIDAS, MEENAKSHI · 2003 to 2013
$67.5MCPML - Project 3: Genome-wide Studies of Adverse EffectsP50GM115279 · NIGMS · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI LOH, MIGNON LEE-CHEUN, RELLING, MARY V · 2015 to 2019
$15.1MSupport for Human Specimen Banking in NCI-Supported Cancer Clinical TrialsU24CA114766 · NCI · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · PI RAMIREZ MILAN, NILSA DEL CARMEN · 2005 to 2014
$14.5MPAARK4Kids-Pharmacogenomics of Anticancer Agents Research in ChildrenU01GM092666 · NIGMS · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI RELLING, MARY V · 2010 to 2014
$8.9MVISION: ValIdated Systematic IntegratiON of epigenomic dataR24DK106766 · NIDDK · PENNSYLVANIA STATE UNIVERSITY, THE · PI BLOBEL, GERD A, BODINE, DAVID M. · 2016 to 2020
$6.2MImpact of genetic variants on gene regulation and 3D genome organization in human diseasesR35GM124820 · NIGMS · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI Feng Yue · 2017 to 2026
$4.0MNEXT GENERATION SEQUENCING ADD-ON-PHARMACOGENOMICS RESEARCH NETWROK (PGRN)U01GM097119 · NIGMS · WASHINGTON UNIVERSITY · PI MARDIS, ELAINE R · 2010 to 2014
$2.6MVisualization, modeling and validation of chromatin interaction dataR01HG009906 · NHGRI · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI YUE, FENG · 2018 to 2022
$2.0MNCI NIH HHS P30 CA021765NCI NIH HHS U01 CA200060NCI NIH HHS U10 CA098413NCI NIH HHS U10 CA098543NCI NIH HHS U10 CA180886NCI NIH HHS U10 CA180899NCI NIH HHS U24 CA114766NHGRI NIH HHS R01 HG009906NHGRI NIH HHS R01 HG011207NIDDK NIH HHS R24 DK106766NIGMS NIH HHS P50 GM115279NIGMS NIH HHS R35 GM124820NIGMS NIH HHS U01 GM092666NIGMS NIH HHS U01 GM097119
Abstract
Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR-Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3 directly regulated CRLF2 and potentiated the JAK-STAT oncogenic effects during leukemogenesis. Taken together, we provide evidence for a distinct mechanism by which a germline noncoding variant contributes to oncogene activation, epigenetic regulation and three-dimensional genome reprogramming.
Indexed as
Genetic Predisposition to DiseasePolymorphism, Single NucleotideChildChromatinEnhancer Elements, GeneticFemaleGATA3 Transcription FactorGenome, HumanHumansJanus KinasesMaleOncogenesPhiladelphia ChromosomePrecursor Cell Lymphoblastic Leukemia-LymphomaProtein BindingReceptors, CytokineChromatinCRLF2 protein, humanGATA3 protein, humanGATA3 Transcription FactorJanus KinasesReceptors, CytokineSTAT Transcription Factors
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