Hyperhomocysteinemia and Genetic Polymorphisms of Methylenetetrahydrofolate Reductase in Acute Lymphoblastic Leukemia Children Treated with High Dose Methotrexate

Abstract

5, I 0-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in DNA methylation and synthesis. MTHFR has two common polymorphisms (C677T and A 1298C), both with reduced enzyme activity and may impair remethylation of homocysteine (Hcy) to methionine resulting in hyperhomocysteinemia. Remethylation of Hcy to methionine and DNA methylation are also affected by methotrexate (MTX) treatment. A combined effect of MTX and reduced MTHFR activity by genetic polymorphisms may lead to the elevation of total Hcy (tHcy). The objective of this study was to examine the correlation between the MTHFR genotype and tHcy in children with acute lymphoblastic leukemia (ALL) receiving high dose MTX (HDMTX). Genotyping of MTHFR was detected by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) method. tHcy was detected by high performance liquid chromatography (HPLC) technique. Our data indicated that after ALL patients treated with HDMTX, tHcy was significantly higher than basal line. The combination of both homozygous mutant alleles (677T/T + 1298C/C) and homozygous plus heterozygous mutant alleles (677T/T + 1298A/C and 677CIT + 1298C/C) were undetected in Thai population studied. The MTHFR polymorphisms may affect the tHcy after MTX treatment (tHcy PMT) especially in the combined heterozygosity (677C/T + 1298A/C) which presented the highest value of tHcy PMT. Therefore the tHcy PMT may be used as a marker for the detection of MTX cytotoxicity in ALL children treated with HDMTX.