Abstract
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)1,2,3. 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 haploinsufficiency, 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.
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Gene Expression Omnibus
Data deposits
The primary SNP microarray data have been deposited in NCBIs Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession numbers GSE9109–GSE9113.
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Acknowledgements
The authors thank Z. Cai for technical help, K. Rakestraw and J. Armstrong for assistance with sequencing, R. Williams and C. Sherr for the provision of Arf null hematopoietic cells and BCR–ABL1 retroviral vectors, O. Heidenreich for providing the SKNO-1 cell line, and D. Campana for providing the OP1 cell line. This study was supported by the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital. C.G.M. was supported by grants from the National Health and Medical Research Council (Australia), the Royal Australasian College of Physicians, and the Haematology Society of Australasia.
Author Contributions C.G.M. collected and extracted clinical samples, performed laboratory assays and analysed data. C.B.M., L.A.P., J.D. and I.R. performed laboratory assays. J.M. analysed SNP array data. D.W., T.P.H., M.M.L., C.-H.P., M.V.R. and S.A.S. collected clinical samples and data. C.G.M and J.R.D designed the study and wrote the manuscript, which was reviewed by all authors.
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Mullighan, C., Miller, C., Radtke, I. et al. BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008). https://doi.org/10.1038/nature06866
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DOI: https://doi.org/10.1038/nature06866
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