N Engl J Med. Volume 360, Issue 5: p.470-480, 29 January 2009, 10.1056/NEJMoa0808253
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.
In order to access Controlled TARGET ALL data using the links below, users must submit an application for Authorized Access via dbGaP as described on dbGaP’s TARGET Study Page. To begin the application process, please view the information and instructions provided on the dbGaP Authorized Access Login Page under “dbGaP Data Download”.
Supplemental Data Files
- GDC Manifests
- Controlled-Access Data Download Manifest (5 Files)
- Open-Access Data Download Manifest (17 Files)
- Copy Number Array
- TARGET ALL P1 Copy Number Array Level 1 Data (Controlled)
- TARGET ALL P1 Copy Number Array Level 2 Data (Controlled)
- TARGET ALL P1 Copy Number Array Level 3 Data
- TARGET ALL P1 Copy Number Array Level 4 Data
- TARGET ALL P1 Copy Number Array Metadata
- Gene Expression
- mRNA-Seq
- TARGET ALL P1 mRNA-seq Level 3 Data
- TARGET ALL P1 mRNA-seq Level 3 Data (Controlled)
- TARGET ALL P1 mRNA-seq Metadata
- Kinome
- TARGET ALL P1 Kinome Metadata
- TARGET ALL P1 Kinome Level 1 Data (Controlled)
- WGS
- TARGET ALL P1 and P2 WGS L3 Data
- TARGET ALL P1 and P2 WGS L3 Data (Controlled)
- TARGET ALL P1 and P2 WGS L4 Data
- TARGET ALL P1 and P2 WGS Metadata
- Additional Information
Additional Resources
- TARGET ALL P1 at SRA (link is external) NCBI
Instructions for Data Download
Open Access Data
- Download the appropriate manifest file from the publication page
- Use the manifest file to download data using the GDC Data Transfer Tool (DTT) or the GDC API
- GDC DTT (Download, User's Guide)
- GDC API (User’s Guide)
Controlled Access Data
- Download the appropriate manifest file from the publication page
- Download a token from the GDC Data Portal
- GDC Data Portal (Launch, User’s Guide)
- Use the manifest file and token to download data using the GDC DTT or the GDC API
- GDC DTT (Download, User’s Guide)
- GDC API (User’s Guide)
For assistance, please contact the GDC Help Desk: support@nci-gdc.datacommons.io