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BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros
Charles G. Mullighan1, Christopher B. Miller1, Letha A. Phillips1, Ina Radtke1, James Dalton1, Jing Ma2, Deborah White3, Timothy P. Hughes2, Michelle M. Le Beau4, Ching-Hon Pui5, Mary V. Relling6, Sheila A. Shurtleff1 and James R. Downing1.
Departments of 1Pathology, 5Oncology and 6Pharmaceutical Sciences and 2The Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN, US; 3Division of Haematology, The Institute for Medical and Veterinary Science, Adelaide, Australia; 4Section of Hematology/Oncology, University of Chicago, Chicago, IL, US.
This paper is published as an advance online publication in Nature. |
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Summary
The Philadelphia chromosome, encoding 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 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 in lymphoid blast crisis of CML. 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 a key event in the development of BCR-ABL1 ALL.
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Data Files (FTP Links)
Below are links to Affymetrix SNP array CEL and SNP call TXT files for the samples reported in the paper. These are (1) 304 diagnostic acute lymphoblastic leukemia samples, 252 of which have 50k Hind, 50k Xba, 250k Sty and 250k Nsp chips, and the remainder have 250k Sty and 250k Nsp only; (2) 50 acute leukemia remissions samples used as references for DNA copy number analysis, all of which have Hind, Xba, Sty and Nsp data; (3) 36 acute leukemia cell lines, which have 250k Sty and Nsp data; and (4) 56 chronic myeloid leukemia samples obtained at remission, chronic phase, accelerated phase or blast crisis (250k Sty and Nsp). SNP calls were generated using Affymetrix Gtype 4.0. The primary SNP microarray data have also been deposited in NCBIs Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession numbers GSE9109-9113.
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