Genes regulating B cell development are mutated in acute lymphoid leukaemia

Chromosomal aberrations are a hallmark of acute lymphoid leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed genome-wide analysis of leukaemic blasts 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 key regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL. PAX5 was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in haploinsufficiency or the generation of hypomorphic alleles. Deletions were also detected in E2A, EBF, LEF1, Ikaros, and Aiolos. These findings demonstrate 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 critical new molecular lesions in cancer. Keywords: disease state analysis *** Due to privacy concerns, the primary SNP array data is no longer available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access using the Web links below. *** 242 acute lymphoid leukaemia samples, 62 reference samples, and 61-64 remission samples were hybridized to 50K_Hind, 50K_Xba, and 250K_Sty SNP arrays.