NUDT15 genotype and erythrocyte thioguanosine levels affect thiopurine metabolite levels into DNA of Japanese children with acute lymphoblastic leukemia

Abstract

Purpose This study aimed to measure thiopurine metabolites—such as deoxythioguanosine incorporated into DNA (DNA-TG)—and erythrocyte thioguanine nucleotides (TGNs) and methyl mercaptopurine (MMPN) levels in Japanese children with acute lymphoblastic leukemia (ALL). This study also evaluated the factors that elevate thiopurine metabolites incorporated into the DNA. Methods DNA-TG, erythrocyte TGNs, and MMPN levels were measured on consecutive clinical visits in 20 Japanese patients with childhood ALL (171 sampling points) using liquid chromatography with tandem mass spectrometry. Nudix hydrolase 15 (NUDT15) was genotyped using Sanger sequencing. Results Of the 20 patients, three had the NUDT15 intermediate activity genotype (*1/*2 or *1/*3), and two had a low activity genotype (*3/*3). The median DNA-TG level was 318 fmol/µg DNA. Erythrocyte TGNs and MMPN levels were 341.4 and 14,136 pmol/8 × 10⁸ red blood cells, respectively. The ratio of DNA-TG/TGNs—which is the active thiopurine metabolite ratio in DNA—was higher in patients with the NUDT15 variant than in the wild type. The DNA-TG/TGNs ratio was inversely correlated with the TGNs level. Erythrocyte TGNs levels were significantly correlated with white blood cell and lymphocyte counts (p = 0.02 and 0.01, respectively), and MMPN levels were significantly correlated with lymphocyte count and aspartate and alanine aminotransferase levels (p = 0.005, 0.0004, and 0.007, respectively). Conclusion The DNA-TG/TGNs ratio differed in each patient. The NUDT15 genotype and erythrocyte TGNs level were affected and elevated the DNA-TG level in Japanese patients with ALL.