Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/52539
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Type: Journal article
Title: BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros
Author: Mullighan, C.
Miller, C.
Radtke, I.
Philips, L.
Dalton, J.
Ma, J.
White, D.
Hughes, T.
Le Beau, M.
Pui, C.
Relling, M.
Shurtleff, S.
Downing, J.
Citation: Nature, 2008; 453(7191):110-114
Publisher: Nature Publishing Group
Issue Date: 2008
ISSN: 0028-0836
1476-4687
Statement of
Responsibility: 
Charles G. Mullighan, Christopher B. Miller, Ina Radtke, Letha A. Phillips, James Dalton, Jing Ma, Deborah White, Timothy P. Hughes, Michelle M. Le Beau, Ching-Hon Pui, Mary V. Relling, Sheila A. Shurtleff & James R. Downing
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). 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.
Keywords: Humans; Fusion Proteins, bcr-abl; Protein Isoforms; Gene Deletion; Protein Structure, Tertiary; Polymorphism, Single Nucleotide; Adult; Child; Ikaros Transcription Factor; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma
RMID: 0020080577
DOI: 10.1038/nature06866
Appears in Collections:Medicine publications

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