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Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Author

Listed:
  • Charles G. Mullighan

    (Departments of Pathology,)

  • Salil Goorha

    (Departments of Pathology,)

  • Ina Radtke

    (Departments of Pathology,)

  • Christopher B. Miller

    (Departments of Pathology,)

  • Elaine Coustan-Smith

    (Oncology,)

  • James D. Dalton

    (Departments of Pathology,)

  • Kevin Girtman

    (Departments of Pathology,)

  • Susan Mathew

    (Departments of Pathology,
    Present address: The Department of Pathology & Laboratory Medicine, New York Presbyterian Hospital, Cornell Campus, 525 East 68th Street, F511, New York, New York 10021, USA.)

  • Jing Ma

    (Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Stanley B. Pounds

    (Biostatistics,)

  • Xiaoping Su

    (Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Ching-Hon Pui

    (Oncology,)

  • Mary V. Relling

    (Pharmaceutical Sciences, and the)

  • William E. Evans

    (Pharmaceutical Sciences, and the)

  • Sheila A. Shurtleff

    (Departments of Pathology,)

  • James R. Downing

    (Departments of Pathology,)

Abstract

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.

Suggested Citation

  • Charles G. Mullighan & Salil Goorha & Ina Radtke & Christopher B. Miller & Elaine Coustan-Smith & James D. Dalton & Kevin Girtman & Susan Mathew & Jing Ma & Stanley B. Pounds & Xiaoping Su & Ching-Hon, 2007. "Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia," Nature, Nature, vol. 446(7137), pages 758-764, April.
    • Handle: RePEc:nat:nature:v:446:y:2007:i:7137:d:10.1038_nature05690
    DOI: 10.1038/nature05690
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    Cited by:

    1. Siobhan Rice & Thomas Jackson & Nicholas T. Crump & Nicholas Fordham & Natalina Elliott & Sorcha O’Byrne & Maria del Mar Lara Fanego & Dilys Addy & Trisevgeni Crabb & Carryl Dryden & Sarah Inglott & D, 2021. "A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Eleanor L. Woodward & Minjun Yang & Larissa H. Moura-Castro & Hilda Bos & Rebeqa Gunnarsson & Linda Olsson-Arvidsson & Diana C. J. Spierings & Anders Castor & Nicolas Duployez & Marketa Zaliova & Jan , 2023. "Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Isabelle Rose Leo & Luay Aswad & Matthias Stahl & Elena Kunold & Frederik Post & Tom Erkers & Nona Struyf & Georgios Mermelekas & Rubin Narayan Joshi & Eva Gracia-Villacampa & Päivi Östling & Olli P. , 2022. "Integrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. R. C. Nayak & K. H. Chang & A. K. Singh & M. Kotliar & M. Desai & A. M. Wellendorf & M. Wunderlich & J. Bartram & B. Mizukawa & M. Cuadrado & P. Dexheimer & A. Barski & X. R. Bustelo & N. N. Nassar & , 2022. "Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Jason P. Wray & Elitza M. Deltcheva & Charlotta Boiers & Simon Е Richardson & Jyoti Bikram Chhetri & John Brown & Sladjana Gagrica & Yanping Guo & Anuradha Illendula & Joost H. A. Martens & Hendrik G., 2022. "Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Xiaohong Li & Steven G Self & Patricia C Galipeau & Thomas G Paulson & Brian J Reid, 2007. "Direct Inference of SNP Heterozygosity Rates and Resolution of LOH Detection," PLOS Computational Biology, Public Library of Science, vol. 3(11), pages 1-10, November.
    7. Robin D. Lee & Sarah A. Munro & Todd P. Knutson & Rebecca S. LaRue & Lynn M. Heltemes-Harris & Michael A. Farrar, 2021. "Single-cell analysis identifies dynamic gene expression networks that govern B cell development and transformation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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