Loss of Nudt15 thiopurine detoxification increases direct DNA damage in hematopoietic stem cells.

ABSTRACT: Thiopurines, such as 6-mercaptopurine (6-MP), are widely used as cytotoxic agents and immunosuppressants for leukemia and autoimmune or inflammatory diseases. A nonsynonymous single nucleotide polymorphism (p.Arg139Cys; R139C) of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene causes the loss of thiopurine detoxification, inducing myelosuppression. To understand such hematotoxicity, we investigate the effects of NUDT15 R139C on hematopoietic stem cells (HSCs) upon thiopurine administration. Using previously established Nudt15^R138C knock-in mice, which mimic myelosuppression in NUDT15^R139C homozygous or heterozygous patients following thiopurine administration, we investigated the numerical changes of HSCs and hematopoietic progenitor cells follo

SUBMITTER: Yamashita N 

PROVIDER: S-EPMC10366091 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature