The genomic basis of childhood T-lineage acute lymphoblastic leukaemia

Petri Pölönen, Danika Giacomo, Anna Eames Seffernick, Abdelrahman Elsayed, Shunsuke Kimura, Francesca Benini, Lindsey E. Montefiori, Brent L. Wood, Jason Xu, Changya Chen, Zhongshan Cheng, Haley Newman, Jason Myers, Ilaria Iacobucci, Elizabeth Li, Jonathan Sussman, Dale Hedges, Yawei Hui, Caroline Diorio, Lahari Uppuluri, David Frank, Yiping Fan, Yunchao Chang, Soheil Meshinchi, Rhonda Ries, Rawan Shraim, Alexander Li, Kathrin M. Bernt, Meenakshi Devidas, Stuart S. Winter, Kimberly P. Dunsmore, Hiroto Inaba, William L. Carroll, Nilsa C. Ramirez, Aaron H. Phillips, Richard W. Kriwacki, Jun J. Yang, Tiffaney L. Vincent, Yaqi Zhao, Pankaj S. Ghate, Jian Wang, Colleen Reilly, Xin Zhou, Mathijs A. Sanders, Junko Takita, Motohiro Kato, Nao Takasugi, Bill H. Chang, Richard D. Press, Mignon Loh, Evadnie Rampersaud, Elizabeth Raetz, Stephen P. Hunger, Kai Tan, Ti-Cheng Chang, Gang Wu, Stanley B. Pounds, Charles G. Mullighan () and David T. Teachey ()
Additional contact information
Petri Pölönen: St Jude Children’s Research Hospital
Danika Giacomo: St Jude Children’s Research Hospital
Anna Eames Seffernick: St Jude Children’s Research Hospital
Abdelrahman Elsayed: St Jude Children’s Research Hospital
Shunsuke Kimura: St Jude Children’s Research Hospital
Francesca Benini: St Jude Children’s Research Hospital
Lindsey E. Montefiori: St Jude Children’s Research Hospital
Brent L. Wood: Laboratory Medicine
Jason Xu: University of Pennsylvania
Changya Chen: Children’s Hospital of Philadelphia
Zhongshan Cheng: St Jude Children’s Research Hospital
Haley Newman: Children’s Hospital of Philadelphia
Jason Myers: St Jude Children’s Research Hospital
Ilaria Iacobucci: St Jude Children’s Research Hospital
Elizabeth Li: Children’s Hospital of Philadelphia
Jonathan Sussman: University of Pennsylvania
Dale Hedges: St Jude Children’s Research Hospital
Yawei Hui: St Jude Children’s Research Hospital
Caroline Diorio: University of Pennsylvania
Lahari Uppuluri: Children’s Hospital of Philadelphia
David Frank: University of Pennsylvania
Yiping Fan: St Jude Children’s Research Hospital
Yunchao Chang: St Jude Children’s Research Hospital
Soheil Meshinchi: Clinical Research Division
Rhonda Ries: Clinical Research Division
Rawan Shraim: Children’s Hospital of Philadelphia
Alexander Li: Children’s Hospital of Philadelphia
Kathrin M. Bernt: University of Pennsylvania
Meenakshi Devidas: St Jude Children’s Research Hospital
Stuart S. Winter: Children’s Minnesota
Kimberly P. Dunsmore: University of Virginia Children’s Hospital
Hiroto Inaba: St Jude Children’s Research Hospital
William L. Carroll: NYU Langone Health
Nilsa C. Ramirez: Nationwide Children’s Hospital
Aaron H. Phillips: St Jude Children’s Research Hospital
Richard W. Kriwacki: St Jude Children’s Research Hospital
Jun J. Yang: St Jude Children’s Research Hospital
Tiffaney L. Vincent: Children’s Hospital of Philadelphia
Yaqi Zhao: St Jude Children’s Research Hospital
Pankaj S. Ghate: St Jude Children’s Research Hospital
Jian Wang: St Jude Children’s Research Hospital
Colleen Reilly: St Jude Children’s Research Hospital
Xin Zhou: St Jude Children’s Research Hospital
Mathijs A. Sanders: Erasmus MC Cancer Institute
Junko Takita: Graduate School of Medicine Kyoto University
Motohiro Kato: Tokyo University
Nao Takasugi: Tokyo University
Bill H. Chang: Oregon Health and Science University
Richard D. Press: Oregon Health and Science University
Mignon Loh: University of Washington
Evadnie Rampersaud: St Jude Children’s Research Hospital
Elizabeth Raetz: NYU Langone Health
Stephen P. Hunger: University of Pennsylvania
Kai Tan: University of Pennsylvania
Ti-Cheng Chang: St Jude Children’s Research Hospital
Gang Wu: St Jude Children’s Research Hospital
Stanley B. Pounds: St Jude Children’s Research Hospital
Charles G. Mullighan: St Jude Children’s Research Hospital
David T. Teachey: University of Pennsylvania

Nature, 2024, vol. 632, issue 8027, 1082-1091

Abstract: Abstract T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07807-0

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