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The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

Nature Genetics volume 49, pages 1211–1218 (2017)Cite this article

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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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Figure 1: The 55 most common targets of sequence mutation in T-ALL.
Figure 2: Recurrently mutated pathways in T-ALL.
Figure 3: A network depicting associations between genetic alterations and T-ALL subgroups and stages of T cell development.
Figure 4: Accelerated leukemogenesis in mutant-MYCN-driven T-ALL.
Figure 5: Signaling mutations in T-ALL.

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References

  1. Hunger, S.P. & Mullighan, C.G. Acute lymphoblastic leukemia in children. N. Engl. J. Med. 373, 1541–1552 (2015).

    CAS  PubMed  Google Scholar 

  2. Aifantis, I., Raetz, E. & Buonamici, S. Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat. Rev. Immunol. 8, 380–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Coustan-Smith, E. et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 10, 147–156 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Inukai, T. et al. Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99-15. Br. J. Haematol. 156, 358–365 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Weng, A.P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Pear, W.S. et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283–2291 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Begley, C.G. et al. Chromosomal translocation in a human leukemic stem-cell line disrupts the T-cell antigen receptor δ-chain diversity region and results in a previously unreported fusion transcript. Proc. Natl. Acad. Sci. USA 86, 2031–2035 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xia, Y. et al. TAL2, a helix-loop-helix gene activated by the (7;9)(q34;q32) translocation in human T-cell leukemia. Proc. Natl. Acad. Sci. USA 88, 11416–11420 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mellentin, J.D., Smith, S.D. & Cleary, M.L. lyl-1, a novel gene altered by chromosomal translocation in T cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif. Cell 58, 77–83 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, J. et al. The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene. Proc. Natl. Acad. Sci. USA 97, 3497–3502 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hatano, M., Roberts, C.W., Minden, M., Crist, W.M. & Korsmeyer, S.J. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 253, 79–82 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Bernard, O.A. et al. A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia. Leukemia 15, 1495–1504 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Homminga, I. et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell 19, 484–497 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Nagel, S., Kaufmann, M., Drexler, H.G. & MacLeod, R.A. The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Cancer Res. 63, 5329–5334 (2003).

    CAS  PubMed  Google Scholar 

  15. Royer-Pokora, B., Loos, U. & Ludwig, W.D. TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Oncogene 6, 1887–1893 (1991).

    CAS  PubMed  Google Scholar 

  16. McGuire, E.A. et al. The t(11;14)(p15;q11) in a T-cell acute lymphoblastic leukemia cell line activates multiple transcripts, including Ttg-1, a gene encoding a potential zinc finger protein. Mol. Cell. Biol. 9, 2124–2132 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Erikson, J. et al. Deregulation of c-myc by translocation of the α-locus of the T-cell receptor in T-cell leukemias. Science 232, 884–886 (1986).

    Article  CAS  PubMed  Google Scholar 

  18. Mullighan, C.G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Clappier, E. et al. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood 110, 1251–1261 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Graux, C. et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat. Genet. 36, 1084–1089 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Van Limbergen, H. et al. Molecular cytogenetic and clinical findings in ETV6/ABL1-positive leukemia. Genes Chromosom. Cancer 30, 274–282 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Hebert, J., Cayuela, J.M., Berkeley, J. & Sigaux, F. Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. Blood 84, 4038–4044 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Remke, M. et al. High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-β and PI3K–AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response. Blood 114, 1053–1062 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gutierrez, A. et al. The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood 118, 4169–4173 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gutierrez, A. et al. Inactivation of LEF1 in T-cell acute lymphoblastic leukemia. Blood 115, 2845–2851 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tosello, V. et al. WT1 mutations in T-ALL. Blood 114, 1038–1045 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Van Vlierberghe, P. et al. ETV6 mutations in early immature human T cell leukemias. J. Exp. Med. 208, 2571–2579 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ntziachristos, P. et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514, 513–517 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Van der Meulen, J. et al. The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood 125, 13–21 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).

    Article  PubMed  CAS  Google Scholar 

  32. Palomero, T. et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat. Med. 13, 1203–1210 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kleppe, M. et al. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat. Genet. 42, 530–535 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gutierrez, A. et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 114, 647–650 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shochat, C. et al. Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J. Exp. Med. 208, 901–908 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zenatti, P.P. et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat. Genet. 43, 932–939 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Flex, E. et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 205, 751–758 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jeong, E.G. et al. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin. Cancer Res. 14, 3716–3721 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Bains, T. et al. Newly described activating JAK3 mutations in T-cell acute lymphoblastic leukemia. Leukemia 26, 2144–2146 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Kontro, M. et al. Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia. Leukemia 28, 1738–1742 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Balgobind, B.V. et al. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood 111, 4322–4328 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. De Keersmaecker, K. et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat. Genet. 45, 186–190 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Van Vlierberghe, P. et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat. Genet. 42, 338–342 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bandapalli, O.R. et al. The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse. Haematologica 99, e188–e192 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vicente, C. et al. Targeted sequencing identifies associations between IL7R–JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica 100, 1301–1310 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Atak, Z.K. et al. Comprehensive analysis of transcriptome variation uncovers known and novel driver events in T-cell acute lymphoblastic leukemia. PLoS Genet. 9, e1003997 (2013).

    Article  PubMed  CAS  Google Scholar 

  47. Winter, S.S. et al. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr. Blood Cancer 62, 1176–1183 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mansour, M.R. et al. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373–1377 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Navarro, J.M. et al. Site- and allele-specific Polycomb dysregulation in T-cell leukaemia. Nat. Commun. 6, 6094 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dees, N.D. et al. MuSiC: identifying mutational significance in cancer genomes. Genome Res. 22, 1589–1598 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Galloway, A. et al. RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence. Science 352, 453–459 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Hodson, D.J. et al. Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia. Nat. Immunol. 11, 717–724 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mansour, M.R. et al. Notch-1 mutations are secondary events in some patients with T-cell acute lymphoblastic leukemia. Clin. Cancer Res. 13, 6964–6969 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vaquerizas, J.M., Kummerfeld, S.K., Teichmann, S.A. & Luscombe, N.M. A census of human transcription factors: function, expression and evolution. Nat. Rev. Genet. 10, 252–263 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Pugh, T.J. et al. The genetic landscape of high-risk neuroblastoma. Nat. Genet. 45, 279–284 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Popov, N., Schülein, C., Jaenicke, L.A. & Eilers, M. Ubiquitylation of the amino terminus of Myc by SCFβ-TrCP antagonizes SCFFbw7-mediated turnover. Nat. Cell Biol. 12, 973–981 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Zhao, X. et al. The N-Myc–DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev. Cell 17, 210–221 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhao, X. et al. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat. Cell Biol. 10, 643–653 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Treanor, L.M. et al. Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential. J. Exp. Med. 211, 701–713 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Taatjes, D.J. The human Mediator complex: a versatile, genome-wide regulator of transcription. Trends Biochem. Sci. 35, 315–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yashiro-Ohtani, Y. et al. Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. Proc. Natl. Acad. Sci. USA 111, E4946–E4953 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Herranz, D. et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20, 1130–1137 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Angulo, I. et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 342, 866–871 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Roberts, K.G. et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N. Engl. J. Med. 371, 1005–1015 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Ye, M. et al. STIP is a critical nuclear scaffolding protein linking USP7 to p53–Mdm2 pathway regulation. Oncotarget 6, 34718–34731 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. Neumann, M., Greif, P.A. & Baldus, C.D. Mutational landscape of adult ETP-ALL. Oncotarget 4, 954–955 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhou, X. et al. Exploring genomic alteration in pediatric cancer using ProteinPaint. Nat. Genet. 48, 4–6 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Parker, M. et al. C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 506, 451–455 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Anders, S., Pyl, P.T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Hoadley, K.A. et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158, 929–944 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kawagoe, H., Kandilci, A., Kranenburg, T.A. & Grosveld, G.C. Overexpression of N-Myc rapidly causes acute myeloid leukemia in mice. Cancer Res. 67, 10677–10685 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Mullighan, C.G. et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N. Engl. J. Med. 360, 470–480 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50, 163–170 (1966).

    CAS  PubMed  Google Scholar 

  78. Fine, J.P. & Gray, R.J. A proportional hazards model for the subdistribution of a competing risk. J. Am. Stat. Assoc. 94, 496–509 (1999).

    Article  Google Scholar 

  79. R Development Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2009).

Download references

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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Authors and 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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  1. Yu Liu
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  11. Xin Zhou
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  18. Cheng Cheng
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  19. Malcolm A Smith
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  20. Jaime Guidry Auvil
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  21. Daniela S Gerhard
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  22. Mary V Relling
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  26. Elizabeth Raetz
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  28. Cheryl L Willman
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  29. Richard C Harvey
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  30. William L Carroll
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  31. Kimberly P Dunsmore
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  32. Stuart S Winter
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  33. Brent L Wood
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  34. Brian P Sorrentino
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  35. James R Downing
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  36. Mignon L Loh
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  37. Stephen P Hunger
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  38. Jinghui Zhang
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  39. Charles G Mullighan
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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.

Corresponding authors

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

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note 1, Supplementary Figures 1–15. (PDF 4225 kb)

Supplementary Tables

Supplementary Tables 1–23. (XLSX 47234 kb)

Supplementary Data Set 1

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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