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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
IKZF1 deletions predict a poor prognosis in children with B-cell progenitor acute lymphoblastic leukemia: a
Yung-Li Yang1, Chia-Cheng Hung, Jiann-Shiuh Chen
1Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Insights
IKZF1 deletions are linked to poor outcomes in childhood acute lymphoblastic leukemia (ALL). Identifying these genetic alterations at diagnosis can help predict treatment failure in pediatric ALL patients.
Area of Science:
- Pediatric Oncology
- Molecular Genetics
Background:
- Relapse occurs in 15-20% of pediatric acute lymphoblastic leukemia (ALL) patients despite risk-directed therapy.
- IKZF1 alterations are associated with poor prognosis in B-cell progenitor ALL.
Purpose of the Study:
- To determine the prognostic significance of IKZF1 deletions in childhood ALL.
- To evaluate IKZF1 deletions as a potential biomarker for treatment failure.
Main Methods:
- Analysis of 242 pediatric B-cell progenitor ALL patients in Taiwan.
- Multiplex quantitative PCR and capillary electrophoresis for IKZF1 allele dose determination.
- High-resolution melting and genomic sequencing for IKZF1 mutation screening.
Main Results:
- IKZF1 deletions were found in 10.7% of patients, predominantly encompassing exons 3-6.
- Patients with IKZF1 deletions showed significantly inferior event-free survival (P < 0.001) and overall survival (P = 0.0016).
- The association between IKZF1 deletions and event-free survival was independent of other prognostic factors (P = 0.003, HR = 2.45).
Conclusions:
- IKZF1 deletions are a significant negative prognostic factor in pediatric B-cell progenitor ALL.
- Detection of IKZF1 deletions can identify high-risk patients needing intensified treatment.
- This study is the first to report on IKZF1 deletions in an Asian population.
Abstract:
Despite current risk-directed therapy, approximately 15-20% of pediatric patients with acute lymphoblastic leukemia (ALL) have relapses. Recent genome-wide analyses have identified that an alteration of IKZF1 is associated with very poor outcomes in B-cell progenitor ALL. In this study, we determined the prognostic significance of IKZF1 deletions in patients with childhood ALL. This study analyzed 242 pediatric B-cell progenitor ALL patients in Taiwan. We developed a simple yet sensitive multiplex quantitative PCR coupled with capillary electrophoresis to accurately determine the allele dose of IKZF1, and high resolution melting was used for mutation screening for all coding exons of IKZF1. Twenty-six (10.7%) pediatric B-cell progenitor ALL patients were found to harbor these deletions. Most of the deletions were broader deletions that encompassed exon 3 to exon 6, consistent with previous reports. Genomic sequencing of IKZF1 was carried out in all cases and no point mutations were identified. Patients with IKZF1 deletions had inferior event-free survival (P < 0.001), and overall survival (P = 0.0016). The association between IKZF1 deletions and event-free survival was independent of age, leukocyte count at presentation, and cytogenetic subtype by multivariate Cox analysis (P = 0.003, hazard ratio = 2.45). This study indicates that detection of IKZF1 deletions upon diagnosis of B-cell progenitor ALL may help to identify patients at risk of treatment failure. IKZF1 deletions could be incorporated as a new high-risk prognostic factor in future treatment protocols. To the best of our knowledge, this is the first study to examine the poor prognosis of IKZF1 deletions in an Asian population.
