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. 2022 Oct;199(2):270-276.
doi: 10.1111/bjh.18375. Epub 2022 Jul 29.

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

Masanori Yoshida  1 , Scott A Brown  2 , Takaya Moriyama  3 , Rina Nishii  3 , Shin-Ichi Tsujimoto  1 , Yuji Yamada  4 , Kaoru Yoshida  1 , Ryota Shirai  1 , Tomoo Osumi  1   4 , Tomoyuki Utano  5 , Reiji Fukano  6 , Ko Kudo  7 , Kimiyoshi Sakaguchi  8 , Yuki Arakawa  9 , Katsuyoshi Koh  9 , Masahiro Sekiguchi  10 , Masahiro Sekimizu  11 , Takako Miyamura  12 , Hisashi Ishida  13 , Takeshi Inukai  14 , Daisuke Tomizawa  4 , Nobutaka Kiyokawa  1 , Motohiro Kato  1   4   10 , Jun J Yang  3   15
Affiliations

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

Masanori Yoshida et al. Br J Haematol. 2022 Oct.

Abstract

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.

Keywords: 6-mercaptopurine; ELISA; NUDT15; NUDT15 expression level; paediatrics.

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Conflict of interest statement

Conflict of Interest

The authors declare no potential conflicts of interest

Figures

Figure 1.
Figure 1.. The NUDT15 genotypes and the average dose of 6-MP.
WT, wild-type; HT, heterozygous variants; Homo, homozygous/bi-allelic variants There was a significant difference in the Kruskal–Wallis test (p < 0.0001). The result of post-hoc comparisons are shown.
Figure 2.
Figure 2.. Difference in NUDT15 expression levels
(A) NUDT15 expression levels in patients with NUDT15 wild-type (WT), heterozygous variants (HT), and homozygous/bi-allelic variants (Homo). (B) NUDT15 expression levels in the respective polymorphisms in heterozygous patients. In (A) and (B), there was a significant difference in the Kruskal–Wallis test (p < 0.0001) and the result of post-hoc comparisons are shown. (C, D) NUDT15 expression levels by gender and age. In (C) and (D), the result of the Kruskal–Wallis test are shown.
Figure 3.
Figure 3.. The correlation between NUDT15 exression levels/NUDT15 genotypes and 6-MP tolerance
The NUDT15 expression levels (log scale) and 6-MP dose in all patients (A), the patients with NUDT15 variants (B), and the patients with homozygous/bi-allelic variants (C) are shown.
See this image and copyright information in PMC

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