title: BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.
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.
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Miller
authors.forename: Ina
authors.initials: I
authors.lastname: Radtke
authors.forename: Letha A
authors.initials: LA
authors.lastname: Phillips
authors.forename: James
authors.initials: J
authors.lastname: Dalton
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Deborah
authors.initials: D
authors.lastname: White
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
mesh_terms: D000328:Adult; D002648:Child; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D051740:Ikaros Transcription Factor / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: C497239:IKZF1 protein, human; D020033:Protein Isoforms; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl