Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia

Abstract

Despite best current therapy, up to 20% of pediatric patients withacute lymphoblastic leukemia (ALL) have a relapse. Recent genomewideanalyses have identified a high frequency of DNA copy-number abnormalitiesin ALL, but the prognostic implications of these abnormalities havenot been defined.We studied a cohort of 221 children with high-riskB-cell-progenitor ALL with the use of single-nucleotide-polymorphismmicroarrays, transcriptional profiling, and resequencing of samplesobtained at diagnosis. Children with known very-high-risk ALL subtypes(i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants)were excluded from this cohort. A copy-number abnormality was identifiedas a predictor of poor outcome, and it was then tested in an independentvalidation cohort of 258 patients with B-cell-progenitor ALL.Morethan 50 recurring copy-number abnormalities were identified, mostcommonly involving genes that encode regulators of B-cell development(in 66.8% of patients in the original cohort); PAX5 was involvedin 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities,we identified a predictor of poor outcome that was validated in theindependent validation cohort. This predictor was strongly associatedwith alteration of IKZF1, a gene that encodes the lymphoid transcriptionfactor IKAROS. The gene-expression signature of the group of patientswith a poor outcome revealed increased expression of hematopoieticstem-cell genes and reduced expression of B-cell-lineage genes, andit was similar to the signature of BCR-ABL1-positive ALL, anotherhigh-risk subtype of ALL with a high frequency of IKZF1 deletion.Geneticalteration of IKZF1 is associated with a very poor outcome in B-cell-progenitorALL.