BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.
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.
Mullighan
Charles G
CG
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Miller
Christopher B
CB
Radtke
Ina
I
Phillips
Letha A
LA
Dalton
James
J
Ma
Jing
J
White
Deborah
D
Hughes
Timothy P
TP
Le Beau
Michelle M
MM
Pui
Ching-Hon
CH
Relling
Mary V
MV
Shurtleff
Sheila A
SA
Downing
James R
JR
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
C497239:IKZF1 protein, human; D020033:Protein Isoforms; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl