Genome-wide analysis of genetic
alterations in acute lymphoblastic
leukaemia
Charles G. Mullighan1, Salil Goorha1, Ina Radtke1, Christopher B. Miller1, Elaine Coustan-Smith1, James D. Dalton1, Kevin Girtman1, Susan Mathew1†, Jing Ma2, Stanley B. Pounds3, Xiaoping Su2, Ching-Hon Pui4, Mary V. Relling5, William E. Evans5, Sheila A. Shurtleff1 and James R. Downing1
Departments of 1Pathology, 3Biostatistics, 4Oncology, 5Pharmaceutical Sciences, and the 2Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, TN, 38105, USA † Susan Mathew's present address is: Susan Mathew, Ph.D. Director, Cytogenetics,
The Department of Pathology & Laboratory Medicine, New York Presbyterian Hospital - Cornell Campus, 525 East 68th Street - F511, N.Y. , N.Y. 10021
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Summary
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 genomicDNAsequencing.Our analyses revealed
deletion, amplification, pointmutation 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. |
