Low NUDT15 expression levels due to biallelic NUDT15 variants and 6‐mercaptopurine intolerance

Abstract

Summary 6‐Mercaptopurine (6‐MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6‐MP–associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA‐incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6‐MP, using sandwich enzyme‐linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6‐MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15‐mediated 6‐MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.

Impact of Pharmacogenomics in Clinical Practice

“…Thiopurine drugs, azathioprine, 6-mercaptopurine, and 6-thioguanine, are widely used to treat cancer, onco-hematological diseases, and autoimmune diseases and to prevent transplant rejection [63]. TPMT, together with nudix hydrolase, is the most im-portant enzyme for thiopurine metabolism [64], and TPMT activity is inversely correlated with the levels of the active metabolites, as observed in children with leukemia [65] and in patients with inflammatory bowel diseases [66]. Patients with high TPMT activity are at risk of poor treatment efficacy due to a low production of active metabolites.…”