Abstract
Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.
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Acknowledgements
We thank the Genome Sequencing Facility, Hartwell Center for Bioinformatics and Biotechnology, and flow cytometry and cell sorting core facility of St. Jude Children's Research Hospital. MSCV-IRES-YFP retroviral vector was provided by G. Grosveld. (St. Jude Children's Research Hospital, Memphis, Tennessee, USA) OP9-DL1 stromal cells were a gift from J.C. Zuniga-Pflucker (University of Toronto, Toronto, Ontario, Canada). This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital, St. Baldrick's Foundation (Scholar Award to C.G.M.), the National Cancer Institute (grants P30 CA021765 (St. Jude Cancer Center Support Grant), U01 CA157937 (to C.L.W. and S.P.H.), U10 CA98543 (to the Children's Oncology Group (COG); Chair's grant and supplement to support the COG ALL TARGET project), U10 CA98413 (to the COG Statistical Center) and U24 CA114766 (to COG; Specimen Banking), Outstanding Investigator Award R35 CA197695 (to C.G.M.), and Contract No. HHSN261200800001E (to C.G.M.)). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
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Y. Liu, Z.W., M.E., X.M., Y. Li and R.C.H. analyzed genomic data. M.R.W., M.R. and P.G. managed genomic data and databases. X.Z. and E.S. prepared data visualization in PeCan. J.E. and Y.S. performed genomic assays. J.M., K.M. and B.P.S. performed experiments. S.B.P., L.S., D.P., C.C. and M.D. performed statistical analysis. M.A.S., J.G.A. and D.S.G. oversaw the NCI TARGET project. M.V.E., N.J.W., E.R., W.L.C., K.P.D. and S.S.W. provided patient data. B.L.W. performed immunophenotyping of leukemia samples. A.J.C. and N.A.H. performed cytogenetic analysis. J.R.D. oversaw genomic analyses. C.L.W., M.L.L. and S.P.H. led and contributed to Children's Oncology Group ALL studies and the ALL TARGET project. J.Z. supervised genomic analysis. C.G.M. analyzed genomic data and wrote the manuscript.
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Uncropped immunoblots for MYCN data. (PDF 209 kb)
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Liu, Y., Easton, J., Shao, Y. et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 49, 1211–1218 (2017). https://doi.org/10.1038/ng.3909
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DOI: https://doi.org/10.1038/ng.3909
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