To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL).
There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL.
We found significantly lower expression of the reduced folate carrier (SLC19A1, an MTX uptake transporter) in E2A-PBX1 ALL, significantly higher expression of breast cancer resistance protein (ABCG2, an MTX efflux transporter) in TEL-AML1 ALL, and lower expression of FPGS (which catalyzes formation of MTXPG) in T-lineage ALL, consistent with lower MTXPG accumulation in these ALL subtypes.
We have identified an hRFC gene point mutation in a transport-defective CCRF-CEM human T-ALL cell line resulting in a lysine to glutamic acid substitution at codon 45 (E45K), which has been identified in other antifolate-resistant sublines (JBC 273:30 189, 1998; JBC 275:30 855, 2000).
Our results suggest that RFC gene expression is far more predictive of methotrexate uptake capacity in B-precursor than T-ALL and that increased copies of chromosome 21 in B-precursor ALL blasts are generally associated with increased RFC transcripts.