title: Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.
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.
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Salil
authors.initials: S
authors.lastname: Goorha
authors.forename: Ina
authors.initials: I
authors.lastname: Radtke
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Miller
authors.forename: Elaine
authors.initials: E
authors.lastname: Coustan-Smith
authors.forename: James D
authors.initials: JD
authors.lastname: Dalton
authors.forename: Kevin
authors.initials: K
authors.lastname: Girtman
authors.forename: Susan
authors.initials: S
authors.lastname: Mathew
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Pounds
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics; D005784:Gene Amplification / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D051757:PAX5 Transcription Factor / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C081976:EBF1 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D015534:Trans-Activators