Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia

Charles G. Mullighan, Xiaoping Su, Jinghui Zhang, Ina Radtke, Letha A.A. Phillips, Christopher B. Miller, Jing Ma, Wei Liu, Cheng Cheng, Brenda A. Schulman, Richard C. Harvey, I. Ming Chen, Robert J. Clifford, William L. Carroll, Gregory Reaman, W. Paul Bowman, Meenakshi Devidas, Daniela S. Gerhard, Wenjian Yang, Mary V. RellingD. Pharm, Sheila A. Shurtleff, Dario Campana, Michael J. Borowitz, Ching Hon Pui, Malcolm Smith, Stephen P. Hunger, Cheryl L. Willman, James R. Downing

Research output: Contribution to journalArticlepeer-review

912 Scopus citations

Abstract

Background: Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. Methods: We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained 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 identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL. Results: More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1- positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. Conclusions: Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progen-itor ALL.

Original languageEnglish
Pages (from-to)470-480
Number of pages11
JournalNew England Journal of Medicine
Volume360
Issue number5
DOIs
StatePublished - 29 Jan 2009

Fingerprint

Dive into the research topics of 'Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia'. Together they form a unique fingerprint.

Cite this