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https://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 |
DOI: | 10.1038/nature06866 |
Published version: | http://dx.doi.org/10.1038/nature06866 |
Appears in Collections: | Aurora harvest Medicine publications |
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