Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.
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.
Mullighan
Charles G
CG
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Goorha
Salil
S
Radtke
Ina
I
Miller
Christopher B
CB
Coustan-Smith
Elaine
E
Dalton
James D
JD
Girtman
Kevin
K
Mathew
Susan
S
Ma
Jing
J
Pounds
Stanley B
SB
Su
Xiaoping
X
Pui
Ching-Hon
CH
Relling
Mary V
MV
Evans
William E
WE
Shurtleff
Sheila A
SA
Downing
James R
JR
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
D004268:DNA-Binding Proteins; C081976:EBF1 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D015534:Trans-Activators