Pediatric lymphoma and leukemia are commonly treated with 6-Mercaptopurine (6-MP). Germline variations in the NUDT15 gene have recently been discovered to be one of the main genetic reasons for the negative effects of 6-MP, such as myelosuppression.

Patients with hypomorphic NUDT15 variations have severe myelosuppression due to the excessive accumulation of DNA-incorporated thioguanine in white blood cells. These variations may affect the protein stability of NUDT15; according to preclinical investigations, however, it hadn’t been specifically characterized in patients. For a study, researchers sought to describe the creation of a series of new monoclonal antibodies against NUDT15 that allowed them to quantitatively measure the protein levels of NUDT15 in 37 patients with acute lymphoblastic leukemia who were receiving treatment with 6-MP (ELISA).

It was shown that the NUDT15 genotype and protein levels were substantially linked (P<0.0001), with homozygous and compound heterozygous individuals expressing very little NUDT15. (r = 0.631, P<0.0001) There was an inverse relationship between NUDT15 protein level and 6-MP tolerance.

In conclusion, the findings provided a phenotypic readout of inherited NUDT15 deficiency by implicating low NUDT15 protein abundance as the molecular foundation for NUDT15-mediated 6-MP intolerance.

Reference: onlinelibrary.wiley.com/doi/10.1111/bjh.18375