Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 360, Issue 5, Pages 470-480Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0808253
Keywords
-
Categories
Funding
- Children's Oncology Group Chair's Award [CA098543]
- Strategic Partnering to Evaluate Cancer Signatures Program [CA114762]
- National Cancer Institute
- National Institute of General Medical Sciences Pharmacogenetics Research Network and Database [U01 GM61393, U01GM61374]
- Cancer Center [21765]
- National Institutes of Health [R01 CA86011, N01-C0-12400]
- Leukemia and Lymphoma Society Specialized Center of Research [7388-06]
- CureSearch National Childhood Cancer Foundation
- National Health and Medical Research Council (Australia)
- Australia) C. J. Martin Traveling Fellowship
- American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital
- NCI
- Becton Dickinson Biosciences
- Xanthus Pharmaceuticals
Ask authors/readers for more resources
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. N Engl J Med 2009;360:470-80.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available