Genetic polymorphism and methylenetetrahydrofolate reductase activity in children with acute lymphoblastic leukemia

Abstract

5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in DNA methylation and synthesis. MTHFR has two common polymorphisms (C677T and A1298C), both reduce enzyme activity and impaire remethylation of homocysteine (Hcy) to methionine resulting in hyperhomocysteinemia. Remethylation of Hcy to methionine and DNA methylation are also affected by methotrexate (MTX) treatmant. A combined effect of MTX and reduced MTHFR activity by 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 phynotype in children with acute lymphoblastic leukemia (ALL) receiving high dose MTX (HDMTX). Genotyping of MTHFR were detected by polymerase chain reaction/ restriction fragment length polymorphism (PCR/RFLP) method. Phynotyping of MTHFR, Hcy, was detected by high performance liquid chromatography (HPLC) technique. Our data indicated that after patients treatedwith HDMTX, tHcy was significantly higher than basal line. The homozygous of both mutant alleles (677TT/1298CC) and one homozygous combined with heterozygous of mutant alleles (677TT/1298AC and 677CT/1298CC) were undetected in Thai population studied. The MTHFR polymorphisms may affect the tHcy after MTX treatment (tHcy PMT) especially in the conbined heterozygosity (677/1298AC).The tHcy PMT may be a marker for MTX cytotoxicity in ALL children treated with HDMTX.