Format

Send to

Choose Destination
Leukemia. 2011 Jan;25(1):66-74. doi: 10.1038/leu.2010.256. Epub 2010 Nov 12.

A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity.

Author information

1
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

Abstract

Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (inhibitory concentration (IC)(50)). In CEU lines, we tested 2,390,203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P<0.001) and gene level (P<0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC(50). The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P=8.1 × 10(-3)), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P=5.5 × 10(-5)). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity.

PMID:
21072045
PMCID:
PMC3097057
DOI:
10.1038/leu.2010.256
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center