THIOPURINE-MEDIATED IMPAIRMENT OF HEMATOPOIEIC STEM AND PROGENITOR CELLS IN NUDT15R138C KNOCK-IN MICE AND POTENTIALITY OF NUDT15 GENOTYPE-BASED PRECISION MEDICINE FOR ACUTE LEUKEMIA
Author(s): ,
Goichi Tatsumi
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan;Department of Hematology and Oncology,Graduate School of Medicine, Kyoto University,Kyoto,Japan
,
Masahiro Kawahara
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan
,
Takayuki Imai
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan
,
Ai Nishishita-Asai
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan
,
Atsushi Nishida
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan
,
Osamu Inatomi
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan
,
Akihiko Yokoyama
Affiliations:
Tsuruoka Metabolomics Laboratory,National Cancer Center,Tsuruoka,Japan
,
Yoichi Kakuta
Affiliations:
Division of Gastroenterology,Tohoku University Graduate School of Medicine,Sendai,Japan
,
Katsuyuki Kito
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan
Akira Andoh
Affiliations:
Department of Medicine,Shiga University of Medical Science,Otsu,Japan
EHA Library. Tatsumi G. Jun 14, 2019; 266258; PF458
Goichi Tatsumi
Goichi Tatsumi
Contributions
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Abstract

Abstract: PF458

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background
Thiopurines are largely used as effective antileukemic agents, but the use of thiopurines is frequently limited by severe adverse effects including myelotoxicity. Recently, non-synonymous single nucleotide polymorphism in NUDT15 which causes p.Arg139Cys (NUDT15R139C) has been reported to be highly prevalent in East Asia and induce severe hematological thiopurine toxicity. However, the impairment of hematopoietic stem and progenitor cells (HSPCs) during thiopurines treatment was not well understood.

Aims
The primary objective is to identify the safe dose of 6-mercaptopurine (MP) for NUDT15R139C positive patients from our newly established mouse model data. The second objective is to develop a NUDT15 genotype-based treatment targeting leukemia cells with NUDT15R139C, using MP maintenance after transplantation.

Methods
We established a knock-in mouse model harboring p.Arg138Cys (Nudt15R138C) which corresponds to the human NUDT15R139C. Each genotype mouse was orally treated with clinically relevant doses of MP, and peripheral blood and bone marrow cells were analyzed by FACS. To assess the tolerance of Nudt15R138C/R138C or Nudt15+/R138C HSPCs to a long administration of lower MP doses, we performed a competitive transplantation assay followed by MP administration. To investigate a novel approach for acute leukemia with homozygous or heterozygous NUDT15R139C, we generated a post-transplantation leukemia recurrence model by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells.

Results
Oral administration of 2 mg/kg MP induced severe or moderate cytopenia in Nudt15R138C/R138C mice or Nudt15+/R138C mice respectively, and MP dose reduction attenuated this myelosuppression, phenocopying clinical observations. Significant acute damage to HSPCs was induced by 5 days of MP administration in Nudt15R138C/R138C mice, although no organs other than bone marrow were histologically damaged. A competitive transplantation assay followed by MP administration revealed that Nudt15R138C/R138C HSPCs and Nudt15+/R138C HSPCs were more impaired than Nudt15+/+ HSPCs after administration of 2 mg/kg, 1 mg/kg, or 0.2 mg/kg MP for 28 days. The MP dose required for a 50% reduction compared to Nudt15+/+ HSPCs was 0.10 - 0.12 mg/kg in Nudt15R138C/R138C HSPCs and 0.19 - 0.23 mg/kg in Nudt15+/R138C HSPCs, respectively. Next, we accessed the impact of MP in mice that reflect the leukemia recurrence after transplantation from a NUDT15 wild-type donor. All mice developed leukemia due to the presence of minimal residual leukemic stem and progenitor cells after acquiring the dominant engraftment of normal BM cells. However, MP successfully prolonged the survival time of post-transplantation Nudt15R138C/R138C leukemia recurrence mice (median: 40 days vs 63 days in control vs 1mg/kg MP, p=0.0002).

Conclusion
Our Nudt15R138C knock-in mouse model provides safer estimates for MP dosing and a caution about the high susceptibility of HPSCs to MP in NUDT15R139C homozygous or heterozygous patients. Moreover, hematopoietic toxicity caused by MP can be converted to a novel treatment against leukemia cells, with support by normal wild-type hematopoiesis. Finally, our data facilitate NUDT15 genotype-based precision medicine for patients receiving thiopurines.

Session topic: 23. Hematopoiesis, stem cells and microenvironment

Keyword(s): Hematopoietic stem and progenitor cells, Targeted therapy

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