NUDT15 polymorphism and NT5C2 and PRPS1 mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells

• DOI: 10.1111/jcmm.16981
• Publication Date: 2021-10-15T17:17:44Z
• Authors: Shinpei Somazu; Yoichi Tanaka; Minori Tamai; Atsushi Watanabe; Keiko Kagami; Masako Abe; Daisuke Harama; Tamao Shinohara; Koshi Akahane; Kumiko Goi; Kanji Sugita; Takaya Moriyama; Jun Yang; Hiroaki Goto; Masayoshi Minegishi; Shotaro Iwamoto; Junko Takita; Takeshi Inukai
• Keywords: Thiopurine methyltransferase; Mercaptopurine

Abstract In chemotherapy for childhood acute lymphoblastic leukaemia (ALL), maintenance therapy consisting of oral daily mercaptopurine and weekly methotrexate is important. NUDT15 variant genotype reportedly highly associated with severe myelosuppression during therapy, particularly in Asian Hispanic populations. It has also been demonstrated that acquired somatic mutations the NT5C2 PRPS1 genes, which are involved thiopurine metabolism, detectable a portion relapsed ALL. To directly confirm significance sensitivity cells intrinsic we investigated 84 B‐cell precursor‐ALL (BCP‐ALL) cell lines. Three 14 lines had homozygous heterozygous diplotypes gene, respectively, while 4 2 were exclusively established from samples at relapse mutations, respectively. Both significantly DNA‐incorporated thioguanine levels after exposure to therapeutic concentration. Considering continuous evaluated vitro 7‐day exposure. Mercaptopurine concentrations lethal 50% comparable serum concentration mercaptopurine. 83 BCP‐ALL 23 T‐ALL The present study provides direct evidence support general principle showing both inherited somatically mutation crucially implicated drug cells.