Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.

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-progenitor ALL.

• Authors: 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 Relling, Sheila A Shurtleff, Dario Campana, Michael J Borowitz, Ching-Hon Pui, Malcolm Smith, Stephen P Hunger, Cheryl L Willman, James R Downing, Children's Oncology Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 360 Issue 5 Pg. 470-80 (Jan 29 2009) ISSN: 1533-4406 [Electronic] United States
• PMID: 19129520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: 2009 Massachusetts Medical Society

Chemical References

• EBF1 protein, human
• IKZF1 protein, human
• PAX5 Transcription Factor
• PAX5 protein, human
• Trans-Activators
• Ikaros Transcription Factor

Topics

• B-Lymphocytes (metabolism)
• Child
• Cohort Studies
• DNA Mutational Analysis
• Drug Resistance, Neoplasm (genetics)
• Gene Deletion
• Gene Expression
• Gene Expression Profiling
• Genotype
• Hematopoietic Stem Cells (metabolism)
• Humans
• Ikaros Transcription Factor (genetics)
• Mutation, Missense
• PAX5 Transcription Factor (genetics)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Prognosis
• Recurrence
• Trans-Activators (genetics)
• Treatment Outcome