BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros

The Philadelphia chromosome, a chromosomal abnormality that encodes BCR - ABL1, is the defining lesion of chronic myelogenous leukaemia ( CML) and a subset of acute lymphoblastic leukaemia (ALL)(1-3). To define oncogenic lesions that cooperate with BCR ABL1 to induce ALL, we performed a genome- wide analysis of diagnostic leukaemia samples from 304 individuals with ALL, including 43 BCR - ABL1 B- progenitor ALLs and 23 CML cases. IKZF1 ( encoding the transcription factor Ikaros) was deleted in 83.7% of BCR - ABL1 ALL, but not in chronic- phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL ( lymphoid blast crisis). The IKZF1 deletions resulted in haploin sufficiency, expression of a dominant- negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant RAG- mediated recombination is responsible for the deletions. These findings suggest that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR - ABL1 ALL.