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

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

Thiopurines are widely used as antileukemia agents and immunosuppressants. Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys ( NUDT15 R139C ) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys (...

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Veröffentlicht in:Leukemia 2020-03, Vol.34 (3), p.882-894
Hauptverfasser: Tatsumi, Goichi, Kawahara, Masahiro, Imai, Takayuki, Nishishita-Asai, Ai, Nishida, Atsushi, Inatomi, Osamu, Yokoyama, Akihiko, Kakuta, Yoichi, Kito, Katsuyuki, Andoh, Akira
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13/1
13/100
13/106
13/31
13/44
13/51
14/63
38/109
38/22
38/77
6-Mercaptopurine
631/208/212/1728
64/60
692/699/1541/1990/283
82/58
Antileukemia agents
Bone marrow
Cancer Research
Critical Care Medicine
Damage tolerance
Dosage
Gene polymorphism
Genotype & phenotype
Hematology
Hematopoietic stem cells
Immunosuppressive agents
Intensive
Internal Medicine
Leukemia
Leukopenia
Medicine
Medicine & Public Health
Oncology
Polymorphism
Precision medicine
Progenitor cells
Stem cell transplantation
Stem cells
Toxicity
Transplantation
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container_issue 3
container_start_page 882
container_title Leukemia
container_volume 34
creator Tatsumi, Goichi
Kawahara, Masahiro
Imai, Takayuki
Nishishita-Asai, Ai
Nishida, Atsushi
Inatomi, Osamu
Yokoyama, Akihiko
Kakuta, Yoichi
Kito, Katsuyuki
Andoh, Akira
description Thiopurines are widely used as antileukemia agents and immunosuppressants. Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys ( NUDT15 R139C ) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys ( Nudt15 R138C ), which corresponds to the human polymorphism. A clinically relevant dose of mercaptopurine (MP) induced lethal cytopenia in Nudt15 R138C -harboring mice. MP dose reduction attenuated the hematopoietic toxicity, phenocopying clinical observations and providing Nudt15 genotype-based tolerable doses of MP. High-dose MP induced acute damage to hematopoietic stem and progenitor cells (HSPCs) in Nudt15 R138C/R138C mice. A competitive transplantation assay revealed that not only Nudt15 R138C/R138C HSPCs, but also Nudt15 +/R138C HSPCs suffered stronger damage than Nudt15 +/+ HSPCs, even by lower-dose MP, after long-term administration. In a Nudt15 genotype-based posttransplantation leukemia recurrence model generated by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells, MP prolonged the survival of mice with posttransplantation Nudt15 R138C/R138C leukemia recurrence. In conclusion, our model will facilitate NUDT15 genotype-based precision medicine by providing safer estimates for MP dosing, and our findings highlighted the high susceptibility of hematopoietic stem cells to MP and suggested that exploiting thiopurine toxicity might be a novel treatment approach for leukemia in NUDT15 R139C -harboring patients.
doi_str_mv 10.1038/s41375-019-0583-9
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Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys ( NUDT15 R139C ) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys ( Nudt15 R138C ), which corresponds to the human polymorphism. A clinically relevant dose of mercaptopurine (MP) induced lethal cytopenia in Nudt15 R138C -harboring mice. MP dose reduction attenuated the hematopoietic toxicity, phenocopying clinical observations and providing Nudt15 genotype-based tolerable doses of MP. High-dose MP induced acute damage to hematopoietic stem and progenitor cells (HSPCs) in Nudt15 R138C/R138C mice. A competitive transplantation assay revealed that not only Nudt15 R138C/R138C HSPCs, but also Nudt15 +/R138C HSPCs suffered stronger damage than Nudt15 +/+ HSPCs, even by lower-dose MP, after long-term administration. In a Nudt15 genotype-based posttransplantation leukemia recurrence model generated by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells, MP prolonged the survival of mice with posttransplantation Nudt15 R138C/R138C leukemia recurrence. In conclusion, our model will facilitate NUDT15 genotype-based precision medicine by providing safer estimates for MP dosing, and our findings highlighted the high susceptibility of hematopoietic stem cells to MP and suggested that exploiting thiopurine toxicity might be a novel treatment approach for leukemia in NUDT15 R139C -harboring patients.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-019-0583-9</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/100 ; 13/106 ; 13/31 ; 13/44 ; 13/51 ; 14/63 ; 38/109 ; 38/22 ; 38/77 ; 6-Mercaptopurine ; 631/208/212/1728 ; 64/60 ; 692/699/1541/1990/283 ; 82/58 ; Antileukemia agents ; Bone marrow ; Cancer Research ; Critical Care Medicine ; Damage tolerance ; Dosage ; Gene polymorphism ; Genotype &amp; phenotype ; Hematology ; Hematopoietic stem cells ; Immunosuppressive agents ; Intensive ; Internal Medicine ; Leukemia ; Leukopenia ; Medicine ; Medicine &amp; Public Health ; Oncology ; Polymorphism ; Precision medicine ; Progenitor cells ; Stem cell transplantation ; Stem cells ; Toxicity ; Transplantation</subject><ispartof>Leukemia, 2020-03, Vol.34 (3), p.882-894</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>2019© The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3329-622966a26e70a28aa078c14dad4ee2c5455e240d5aca971be41fd0c8c935af1e3</citedby><cites>FETCH-LOGICAL-c3329-622966a26e70a28aa078c14dad4ee2c5455e240d5aca971be41fd0c8c935af1e3</cites><orcidid>0000-0001-5886-2381 ; 0000-0002-2721-7571 ; 0000-0002-7042-009X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41375-019-0583-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41375-019-0583-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids></links><search><creatorcontrib>Tatsumi, Goichi</creatorcontrib><creatorcontrib>Kawahara, Masahiro</creatorcontrib><creatorcontrib>Imai, Takayuki</creatorcontrib><creatorcontrib>Nishishita-Asai, Ai</creatorcontrib><creatorcontrib>Nishida, Atsushi</creatorcontrib><creatorcontrib>Inatomi, Osamu</creatorcontrib><creatorcontrib>Yokoyama, Akihiko</creatorcontrib><creatorcontrib>Kakuta, Yoichi</creatorcontrib><creatorcontrib>Kito, Katsuyuki</creatorcontrib><creatorcontrib>Andoh, Akira</creatorcontrib><title>Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15R138C knock-in mice</title><title>Leukemia</title><addtitle>Leukemia</addtitle><description>Thiopurines are widely used as antileukemia agents and immunosuppressants. Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys ( NUDT15 R139C ) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys ( Nudt15 R138C ), which corresponds to the human polymorphism. A clinically relevant dose of mercaptopurine (MP) induced lethal cytopenia in Nudt15 R138C -harboring mice. MP dose reduction attenuated the hematopoietic toxicity, phenocopying clinical observations and providing Nudt15 genotype-based tolerable doses of MP. High-dose MP induced acute damage to hematopoietic stem and progenitor cells (HSPCs) in Nudt15 R138C/R138C mice. A competitive transplantation assay revealed that not only Nudt15 R138C/R138C HSPCs, but also Nudt15 +/R138C HSPCs suffered stronger damage than Nudt15 +/+ HSPCs, even by lower-dose MP, after long-term administration. In a Nudt15 genotype-based posttransplantation leukemia recurrence model generated by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells, MP prolonged the survival of mice with posttransplantation Nudt15 R138C/R138C leukemia recurrence. In conclusion, our model will facilitate NUDT15 genotype-based precision medicine by providing safer estimates for MP dosing, and our findings highlighted the high susceptibility of hematopoietic stem cells to MP and suggested that exploiting thiopurine toxicity might be a novel treatment approach for leukemia in NUDT15 R139C -harboring patients.</description><subject>13/1</subject><subject>13/100</subject><subject>13/106</subject><subject>13/31</subject><subject>13/44</subject><subject>13/51</subject><subject>14/63</subject><subject>38/109</subject><subject>38/22</subject><subject>38/77</subject><subject>6-Mercaptopurine</subject><subject>631/208/212/1728</subject><subject>64/60</subject><subject>692/699/1541/1990/283</subject><subject>82/58</subject><subject>Antileukemia agents</subject><subject>Bone marrow</subject><subject>Cancer Research</subject><subject>Critical Care Medicine</subject><subject>Damage tolerance</subject><subject>Dosage</subject><subject>Gene polymorphism</subject><subject>Genotype &amp; 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Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys ( NUDT15 R139C ) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys ( Nudt15 R138C ), which corresponds to the human polymorphism. A clinically relevant dose of mercaptopurine (MP) induced lethal cytopenia in Nudt15 R138C -harboring mice. MP dose reduction attenuated the hematopoietic toxicity, phenocopying clinical observations and providing Nudt15 genotype-based tolerable doses of MP. High-dose MP induced acute damage to hematopoietic stem and progenitor cells (HSPCs) in Nudt15 R138C/R138C mice. A competitive transplantation assay revealed that not only Nudt15 R138C/R138C HSPCs, but also Nudt15 +/R138C HSPCs suffered stronger damage than Nudt15 +/+ HSPCs, even by lower-dose MP, after long-term administration. In a Nudt15 genotype-based posttransplantation leukemia recurrence model generated by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells, MP prolonged the survival of mice with posttransplantation Nudt15 R138C/R138C leukemia recurrence. In conclusion, our model will facilitate NUDT15 genotype-based precision medicine by providing safer estimates for MP dosing, and our findings highlighted the high susceptibility of hematopoietic stem cells to MP and suggested that exploiting thiopurine toxicity might be a novel treatment approach for leukemia in NUDT15 R139C -harboring patients.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><doi>10.1038/s41375-019-0583-9</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-5886-2381</orcidid><orcidid>https://orcid.org/0000-0002-2721-7571</orcidid><orcidid>https://orcid.org/0000-0002-7042-009X</orcidid><oa>free_for_read</oa></addata></record>
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subjects 13/1
13/100
13/106
13/31
13/44
13/51
14/63
38/109
38/22
38/77
6-Mercaptopurine
631/208/212/1728
64/60
692/699/1541/1990/283
82/58
Antileukemia agents
Bone marrow
Cancer Research
Critical Care Medicine
Damage tolerance
Dosage
Gene polymorphism
Genotype & phenotype
Hematology
Hematopoietic stem cells
Immunosuppressive agents
Intensive
Internal Medicine
Leukemia
Leukopenia
Medicine
Medicine & Public Health
Oncology
Polymorphism
Precision medicine
Progenitor cells
Stem cell transplantation
Stem cells
Toxicity
Transplantation
title Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15R138C knock-in mice
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