Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy.

ABSTRACT: Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15-guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15^-/- mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15^-/- mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15^-/- mice

SUBMITTER: Nishii R 

PROVIDER: S-EPMC5981167 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature