Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15R138C knock-in mice

Tatsumi, Goichi; Kawahara, M.; Imai, Toshio; Nishishita-Asai, Ai; Nishida, Atsushi; Inatomi, Osamu; Yokoyama, Akihiko; Kakuta, Yoichi; Kiura, Katsuyuki; Andoh, Akira

doi:10.1038/s41375-019-0583-9

Cited by 10 publications

(16 citation statements)

References 42 publications

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“…25 In mice with the homologous mutation corresponding to the human NUDT15 R139C variant, a high dose of 6-MP (2 mg/kg) damages hematopoietic stem cells and progenitor cells and causes lethal leukopenia. 26 NUDT15 is an important enzyme in the metabolism of thiopurine, but its physiological function in vivo is still unknown. NUDT15 can hydrolyze 8-oxo-dGTP, one of the most common oxidative dNTP generated by oxidative stress and a potent mutagenic substrate for DNA synthesis, to 8-oxo-dGDP or 8-oxo-dGMP, 27 but this effect of NUDT15 is of minor importance in vivo because depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA in vivo.…”

Section: Role Of Nudt15mentioning

confidence: 99%

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NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

Matsuoka

2020

Intest Res

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Thiopurine has been used to maintain remission and to reduce antidrug antibody formation in monoclonal antibody therapy in patients with inflammatory bowel disease (IBD). The use of thiopurine is limited by side effects such as leukopenia. Thiopurine S-methyltransferase (TPMT) variants are associated with thiopurine-induced leukopenia in Westerners, but the frequency of the risk alleles is low in Asians. Recently, a variant in the nudix hydrolase 15 (NUDT15) gene (R139C, c415C > T) was reported to be associated with early severe leukopenia in Asians. NUDT15 is an enzyme that converts 6-thio-(deoxy)guanosine triphosphate (6-T(d)GTP) to 6-thio-(deoxy)guanosine monophosphate (6-T(d)GMTP). The R139C variant impairs the stability of the protein and increases incorporation of 6-TGTP and 6-TdGTP into RNA and DNA, respectively, resulting in leukopenia. The frequency of C/C, C/T, and T/T are approximately 80%, 20%, and 1%, respectively in East Asians. Early leukopenia occurred in less than 3% of patients with C/C and in around 20% of those with C/T, whereas it occurred in almost all patients with T/T. Patients homozygous for this variant also develop severe hair loss. The measurement of NUDT R139C can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of IBD.

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Section: Role Of Nudt15mentioning

confidence: 99%

“…in vivo , administration of 6-MP to NUDT15 knockout mice increased the incorporation of 6-TdGTP into DNA [ 25 ]. In mice with the homologous mutation corresponding to the human NUDT15 R139C variant, a high dose of 6-MP (2 mg/kg) damages hematopoietic stem cells and progenitor cells and causes lethal leukopenia [ 26 ].…”

Section: Role Of Nudt15mentioning

confidence: 99%

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

Matsuoka

2020

Intest Res

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“…4 We recently established knock-in mice harboring a p.Arg138Cys mutation (Nudt15 R138C ), which corresponds to human NUDT15 R139C, and demonstrated that thiopurine administration causes hematopoietic stem cell (HSC) toxicity in Nudt15 þ/ R138C or Nudt15 R138C/R138C mice (see Supplementary Methods). 6 In this study using our mouse model, we investigated whether thiopurine use during pregnancy differentially affects offspring, based on their NUDT15 genotype.…”

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confidence: 99%

“…Our previous report demonstrated that the long-term (>2 months) survivable dose of mercaptopurine (MP) is 1.0 mg/kg for Nudt15 þ/þ , 0.5 mg/kg for Nudt15 þ/R138C , and 0.2 mg/kg for Nudt15 R138C/R138C adult mice. 6 Thus, we administered the same doses of MP to Nudt15 þ/R138C or Nudt15 þ/þ pregnant mice, respectively, and then characterized the Nudt15 genotypes of the neonatal mice. Nudt15 þ/R138C female mice that were mated with Nudt15 þ/R138C male mice generated neonatal mice in a Mendelian fashion under 0 mg/kg and 0.1 mg/kg MP treatment (see Supplementary Methods).…”

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confidence: 99%

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Thiopurine Use During Pregnancy Has Deleterious Effects on Offspring in Nudt15R138C Knock-In Mice

Imai

Kawahara

Tatsumi

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Individualized Use of 6‐Mercaptopurine in Chinese Children with ALL: A Multicenter Randomized Controlled Trial

Zhou,

Wang,

Sun

et al. 2023

Clin Pharma and Therapeutics

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Continuous 6‐mercaptopurine (6‐MP) dose titration is necessary because of its narrow therapeutic index and frequently encountered dose‐limiting hematopoietic toxicity. However, evidence‐based guidelines for gene‐based 6‐MP dosing have not been established for Chinese children with acute lymphoblastic leukemia (ALL). This multicenter, randomized, open‐label, active‐controlled clinical trial randomly assigned Chinese children with low‐ or intermediate‐risk ALL in a 1:1 ratio to receive TPMT–NUDT15 gene–based dosing of 6‐MP (N = 44, 10 to 50 mg/m2/day) or standard dosing (N = 44, 50 mg/m2/day) during maintenance therapy. The primary endpoint was the incidence of 6‐MP myelosuppression in both groups. Secondary endpoints included frequencies of 6‐MP hepatotoxicity, duration of myelosuppression and leukopenia, event‐free survival, and steady‐state concentrations of active metabolites (6‐thioguaninenucleotides and 6‐methylmercaptopurine nucleotides) in erythrocytes. A 2.2‐fold decrease in myelosuppression, the primary endpoint, was observed in the gene‐based–dose group using approximately 50% of the standard initial 6‐MP dose (odds ratio, 0.26, 95% confidence interval, 0.11 to 0.64; p = 0.003). Patients in the gene‐based–dose group had a significantly lower risk of developing thiopurine‐induced myelosuppression and leukopenia (p = 0.015 and p = 0.022, respectively). No significant differences were observed in the secondary endpoints of the incidence of hepatotoxicity and steady‐state concentrations of active metabolites in erythrocytes between the two groups. TPMT‐ and NUDT15‐based dosing of 6‐MP will significantly contribute toward further reducing the incidence of leukopenia in Chinese children with ALL. This trial is registered at www.clinicaltrial.gov as #NCT04228393.

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Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15R138C knock-in mice

Cited by 10 publications

References 42 publications

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

Thiopurine Use During Pregnancy Has Deleterious Effects on Offspring in Nudt15R138C Knock-In Mice

Individualized Use of 6‐Mercaptopurine in Chinese Children with ALL: A Multicenter Randomized Controlled Trial

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