Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

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 Pui, Mary V. Relling, William E. Evans, Sheila A. Shurtleff and James R. Downing ()
Additional contact information
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,
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,

Nature, 2007, vol. 446, issue 7137, 758-764

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05690

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