The genomic basis of childhood T-lineage acute lymphoblastic leukaemia

• 成果类型: Article
• 署名作者: Polonen, Petri; Di Giacomo, Danika; Seffernick, Anna Eames; Elsayed, Abdelrahman; Kimura, Shunsuke; Benini, Francesca; Montefiori, Lindsey E.; Wood, Brent L.; Xu, Jason; Chen, Changya; Cheng, Zhongshan; Newman, Haley; Myers, Jason; Iacobucci, Ilaria; Li, Elizabeth; Sussman, Jonathan; Hedges, Dale; Hui, Yawei; Diorio, Caroline; Uppuluri, Lahari; Frank, David; Fan, Yiping; Chang, Yunchao; Meshinchi, Soheil; Ries, Rhonda; Shraim, Rawan; Li, Alexander; Bernt, Kathrin M.; Devidas, Meenakshi; Winter, Stuart S.; Dunsmore, Kimberly P.; Inaba, Hiroto; Carroll, William L.; Ramirez, Nilsa C.; Phillips, Aaron H.; Kriwacki, Richard W.; Yang, Jun J.; Vincent, Tiffaney L.; Zhao, Yaqi; Ghate, Pankaj S.; Wang, Jian; Reilly, Colleen; Zhou, Xin; Sanders, Mathijs A.; Takita, Junko; Kato, Motohiro; Takasugi, Nao; Chang, Bill H.; Press, Richard D.; Loh, Mignon; Rampersaud, Evadnie; Raetz, Elizabeth; Hunger, Stephen P.; Tan, Kai; Chang, Ti-Cheng; Wu, Gang; Pounds, Stanley B.; Mullighan, Charles G.; Teachey, David T.
• 署名单位: St Jude Children's Research Hospital; University of Perugia; St Jude Children's Research Hospital; Sapienza University Rome; IRCCS Bambino Gesu; Children's Hospital Los Angeles; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; St Jude Children's Research Hospital; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Fred Hutchinson Cancer Center; St Jude Children's Research Hospital; Children's Hospitals & Clinics of Minnesota; Children's Hospitals & Clinics of Minnesota; University of Virginia; St Jude Children's Research Hospital; NYU Langone Medical Center; NYU Langone Medical Center; University System of Ohio; Ohio State University; Nationwide Childrens Hospital; St Jude Children's Research Hospital; University of Tennessee System; University of Tennessee Health Science Center; University of Tennessee System; University of Tennessee Health Science Center; St Jude Children's Research Hospital; St Jude Children's Research Hospital; Erasmus University Rotterdam; Erasmus MC; Erasmus MC Cancer Institute; Wellcome Trust Sanger Institute; Kyoto University; University of Tokyo; Oregon Health & Science University; Oregon Health & Science University; Seattle Children's Hospital; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Seattle Children's Hospital; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3692
• DOI: 10.1038/s41586-024-07807-0
• 发表日期: 2024-08-29
• 页码: 1082-+
• 关键词: cell; cancer; landscape; promoter

摘要

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour(1) that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation(2,3). Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.