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.
journal_name
Naturejournal_title
Natureauthors
Mullighan CG,Miller CB,Radtke I,Phillips LA,Dalton J,Ma J,White D,Hughes TP,Le Beau MM,Pui CH,Relling MV,Shurtleff SA,Downing JRdoi
10.1038/nature06866subject
Has Abstractpub_date
2008-05-01 00:00:00pages
110-4issue
7191eissn
0028-0836issn
1476-4687pii
nature06866journal_volume
453pub_type
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