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.

Author information

Affiliations

  1. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Yu Liu
    • , John Easton
    • , Ying Shao
    • , Zhaoming Wang
    • , Michael Edmonson
    • , Xin Zhou
    • , Xiaotu Ma
    • , Edgar Sioson
    • , Yongjin Li
    • , Michael Rusch
    • , Pankaj Gupta
    •  & Jinghui Zhang
  2. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Ying Shao
    • , Mark R Wilkinson
    • , Kelly McCastlain
    • , James R Downing
    •  & Charles G Mullighan
  3. Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Jamie Maciaszek
    •  & Brian P Sorrentino
  4. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Stanley B Pounds
    • , Lei Shi
    • , Deqing Pei
    •  & Cheng Cheng
  5. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.

    • Malcolm A Smith
  6. Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA.

    • Jaime Guidry Auvil
    •  & Daniela S Gerhard
  7. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Mary V Relling
  8. University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Naomi J Winick
  9. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Andrew J Carroll
  10. Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

    • Nyla A Heerema
  11. Department of Pediatrics, Huntsman Cancer Institute and Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.

    • Elizabeth Raetz
  12. Department of Biostatistics, Colleges of Medicine, Public Health & Health Profession, University of Florida, Gainesville, Florida, USA.

    • Meenakshi Devidas
  13. Department of Pathology, The Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA.

    • Cheryl L Willman
    •  & Richard C Harvey
  14. Department of Pediatrics, Perlmutter Cancer Center, New York University Medical Center, New York, New York, USA.

    • William L Carroll
  15. Health Sciences Center, University of Virginia, Charlottesville, Virginia, USA.

    • Kimberly P Dunsmore
  16. Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico, USA.

    • Stuart S Winter
  17. Seattle Cancer Care Alliance, Seattle, Washington, USA.

    • Brent L Wood
  18. Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California, USA.

    • Mignon L Loh
  19. Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Stephen P Hunger

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stephen P Hunger or Jinghui Zhang or Charles G Mullighan.

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    Uncropped immunoblots for MYCN data.

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https://doi.org/10.1038/ng.3909

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