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

Nature volume 453, pages 110–114 (2008)Cite this article

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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Figure 1: IKZF1 deletions in BCR–ABL1 ALL.
Figure 2: Ikaros isoforms in ALL blasts.
Figure 3: IKZF1 deletions in blast crisis CML.

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Accession codes

Primary accessions

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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Authors and Affiliations

  1. Departments of Pathology,,

    Charles G. Mullighan, Christopher B. Miller, Ina Radtke, Letha A. Phillips, James Dalton, Sheila A. Shurtleff & James R. Downing

  2. Oncology and,,

    Ching-Hon Pui

  3. Pharmaceutical Sciences and,,

    Mary V. Relling

  4. The Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA ,

    Jing Ma

  5. Division of Haematology, The Institute for Medical and Veterinary Science, Adelaide, South Australia 5000, Australia,

    Deborah White & Timothy P. Hughes

  6. Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, USA ,

    Michelle M. Le Beau

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Correspondence to James R. Downing.

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The file contains Supplementary Results; Supplementary Tables 1-7; Supplementary Figures 1-8 with Legends and additional references. (PDF 2855 kb)

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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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