The genomic basis of childhood T-lineage acute lymphoblastic leukaemia

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...

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Vydáno v:	Nature (London) Ročník 632; číslo 8027; s. 1082 - 1091
Hlavní autoři:	Pölönen, 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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 29.08.2024 Nature Publishing Group
Témata:	38 38/91 45 631/114/2401 631/67/1990/283/2125 631/67/68 631/67/69 Acute lymphoblastic leukemia Cell culture Child Childhood Children Chromatin Chromatin - genetics Chromatin - metabolism Deregulation Enhancer Elements, Genetic - genetics Enhancers Epigenomics Female Gene expression Gene Expression Regulation, Leukemic Gene sequencing Genes Genetic diversity Genome, Human - genetics Genomes Genomic analysis Genomics Hematopoietic stem cells Humanities and Social Sciences Humans Leukemia Lymphocytes Lymphocytes T Male Medical prognosis multidisciplinary Mutation Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology Precursors Remission Science Science (multidisciplinary) Single-Cell Analysis Stem cells T cell receptors T-Lymphocytes - cytology T-Lymphocytes - pathology Topology Transcriptome - genetics Transcriptomes
ISSN:	0028-0836, 1476-4687, 1476-4687
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Popis
Shrnutí:	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. Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Equal contribution M.L., E.R., S.P.H., J.J.Y., M.D., H.I., S.W., K.D., W.L.C, N.C.R, K.B., C.D., L.U., D.F., S.M., R.R., A.L., T.L.V., P.S.G., M.A.S., J.T., M.K., N.T., B.H.C., R.D.P., Y.Z., provided patient samples and collected data. P.P., Z.C., J.M, Y.H., Y.F., D.H., E.R, preprocessed data. P.P., T.C.C, G.W., H.N., R.S., analyzed genomic data. P.P., A.E.S., A.E, S.B.P. performed statistical analysis. P.P., J.X., C.C., E.L., J.S., A.L., K.T analyzed single cell RNA data. P.P., J.W., C.R., X.Z., generated cloud-based visualizations. R.R., S.M., T.V isolated DNA/RNA, J.X., C.C, performed single cell library preparation and sequencing, D.D.G. and L.E.M. performed HiCHIP and ATACseq, R.D.P. performed targeted amplicon sequencing, F.B., S.K., performed long read sequencing, S.K. engineered MED12 knock-out cells, Y.C. performed western blotting, F.B., I.I., S.K., performed luciferase report assays. B.L.W analyzed flow cytometry data. P.P., C.G.M., D.T.T. designed the study and wrote the manuscript. Author Contributions
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-024-07807-0