@article{52388fad2d9144b5a827fc8b40c642a4,
title = "Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation",
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.",
author = "Hongbo Yang and Hui Zhang and Yu Luan and Tingting Liu and Wentao Yang and Roberts, {Kathryn G.} and Qian, {Mao xiang} and Bo Zhang and Wenjian Yang and Virginia Perez-Andreu and Jie Xu and Sriranga Iyyanki and Da Kuang and Stasiak, {Lena A.} and Reshmi, {Shalini C.} and Julie Gastier-Foster and Colton Smith and Pui, {Ching Hon} and Evans, {William E.} and Hunger, {Stephen P.} and Platanias, {Leonidas C.} and Relling, {Mary V.} and Mullighan, {Charles G.} and Loh, {Mignon L.} and Feng Yue and Yang, {Jun J.}",
note = "Funding Information: This work was supported by the National Institutes of Health (grant nos. CA21765, CA98543, CA114766, CA98413, CA180886, CA180899, GM92666, GM115279 and GM097119) and the American Lebanese Syrian Associated Charities. H.Z. is a St. Baldrick{\textquoteright}s International Scholar (grant no. 581580). S.P.H. is the Jeffrey E. Perelman Distinguished Chair in Pediatrics at The Children{\textquoteright}s Hospital of Philadelphia. M.L.L. is the University of California San Francisco Benioff Chair of Children{\textquoteright}s Health and the Deborah and Arthur Ablin Chair of Pediatric Molecular Oncology. F.Y. is supported by grant nos. 1R35GM124820, R01HG009906, U01CA200060 and R24DK106766. We thank the patients and parents who participated in the St. Jude and COG clinical trials included in this study, the clinicians and research staff at St. Jude Children{\textquoteright}s Research Hospital and COG institutions. Funding Information: This work was supported by the National Institutes of Health (grant nos. CA21765, CA98543, CA114766, CA98413, CA180886, CA180899, GM92666, GM115279 and GM097119) and the American Lebanese Syrian Associated Charities. H.Z. is a St. Baldrick?s International Scholar (grant no. 581580). S.P.H. is the Jeffrey E. Perelman Distinguished Chair in Pediatrics at The Children?s Hospital of Philadelphia. M.L.L. is the University of California San Francisco Benioff Chair of Children?s Health and the Deborah and Arthur Ablin Chair of Pediatric Molecular Oncology. F.Y. is supported by grant nos. 1R35GM124820, R01HG009906, U01CA200060 and R24DK106766. We thank the patients and parents who participated in the St. Jude and COG clinical trials included in this study, the clinicians and research staff at St. Jude Children?s Research Hospital and COG institutions. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = feb,
doi = "10.1038/s41588-021-00993-x",
language = "English (US)",
volume = "54",
pages = "170--179",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",
}
