Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate

Abstract Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient’s age, which...

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Autores principales:	Kazuki Taoka, Shunya Arai, Keisuke Kataoka, Masataka Hosoi, Masashi Miyauchi, Sho Yamazaki, Akira Honda, Wei Aixinjueluo, Takashi Kobayashi, Keiki Kumano, Akihide Yoshimi, Makoto Otsu, Akira Niwa, Tatsutoshi Nakahata, Hiromitsu Nakauchi, Mineo Kurokawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Chronic Myelomonocytic Leukemia (CMML) Clodronate Liposomes Drug Testing Systems Teratoma Hematopoietic Progenitor Cells (HPCs) Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ca6c14c5e42546afa52dabe821a5a19d
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spelling	oai:doaj.org-article:ca6c14c5e42546afa52dabe821a5a19d2021-12-02T15:07:44ZUsing patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate10.1038/s41598-018-34193-12045-2322https://doaj.org/article/ca6c14c5e42546afa52dabe821a5a19d2018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34193-1https://doaj.org/toc/2045-2322Abstract Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient’s age, which is usually not eligible for transplantation. Comprehensive analysis of CMML pathophysiology and the development of therapeutic agents have been limited partly due to the lack of cell lines in CMML and the limited developments of mouse models. After successfully establishing patient’s derived disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with CMML, we utilized these CMML-iPSCs to achieve hematopoietic re-differentiation in vitro, created a humanized CMML mouse model via teratomas, and developed a drug-testing system. The clinical characteristics of CMML were recapitulated following hematopoietic re-differentiation in vitro and a humanized CMML mouse model in vivo. The drug-testing system using CMML-iPSCs identified a MEK inhibitor, a Ras inhibitor, and liposomal clodronate as potential drugs for treating CMML. Clodronate is a drug commonly used as a bisphosphonate for osteoporosis. In this study, the liposomalization of clodronate enhanced its effectiveness in these assays, suggesting that this variation of clodronate may be adopted as a repositioned drug for CMML therapy.Kazuki TaokaShunya AraiKeisuke KataokaMasataka HosoiMasashi MiyauchiSho YamazakiAkira HondaWei AixinjueluoTakashi KobayashiKeiki KumanoAkihide YoshimiMakoto OtsuAkira NiwaTatsutoshi NakahataHiromitsu NakauchiMineo KurokawaNature PortfolioarticleChronic Myelomonocytic Leukemia (CMML)Clodronate LiposomesDrug Testing SystemsTeratomaHematopoietic Progenitor Cells (HPCs)MedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chronic Myelomonocytic Leukemia (CMML) Clodronate Liposomes Drug Testing Systems Teratoma Hematopoietic Progenitor Cells (HPCs) Medicine R Science Q
spellingShingle	Chronic Myelomonocytic Leukemia (CMML) Clodronate Liposomes Drug Testing Systems Teratoma Hematopoietic Progenitor Cells (HPCs) Medicine R Science Q Kazuki Taoka Shunya Arai Keisuke Kataoka Masataka Hosoi Masashi Miyauchi Sho Yamazaki Akira Honda Wei Aixinjueluo Takashi Kobayashi Keiki Kumano Akihide Yoshimi Makoto Otsu Akira Niwa Tatsutoshi Nakahata Hiromitsu Nakauchi Mineo Kurokawa Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate
description	Abstract Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient’s age, which is usually not eligible for transplantation. Comprehensive analysis of CMML pathophysiology and the development of therapeutic agents have been limited partly due to the lack of cell lines in CMML and the limited developments of mouse models. After successfully establishing patient’s derived disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with CMML, we utilized these CMML-iPSCs to achieve hematopoietic re-differentiation in vitro, created a humanized CMML mouse model via teratomas, and developed a drug-testing system. The clinical characteristics of CMML were recapitulated following hematopoietic re-differentiation in vitro and a humanized CMML mouse model in vivo. The drug-testing system using CMML-iPSCs identified a MEK inhibitor, a Ras inhibitor, and liposomal clodronate as potential drugs for treating CMML. Clodronate is a drug commonly used as a bisphosphonate for osteoporosis. In this study, the liposomalization of clodronate enhanced its effectiveness in these assays, suggesting that this variation of clodronate may be adopted as a repositioned drug for CMML therapy.
format	article
author	Kazuki Taoka Shunya Arai Keisuke Kataoka Masataka Hosoi Masashi Miyauchi Sho Yamazaki Akira Honda Wei Aixinjueluo Takashi Kobayashi Keiki Kumano Akihide Yoshimi Makoto Otsu Akira Niwa Tatsutoshi Nakahata Hiromitsu Nakauchi Mineo Kurokawa
author_facet	Kazuki Taoka Shunya Arai Keisuke Kataoka Masataka Hosoi Masashi Miyauchi Sho Yamazaki Akira Honda Wei Aixinjueluo Takashi Kobayashi Keiki Kumano Akihide Yoshimi Makoto Otsu Akira Niwa Tatsutoshi Nakahata Hiromitsu Nakauchi Mineo Kurokawa
author_sort	Kazuki Taoka
title	Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate
title_short	Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate
title_full	Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate
title_fullStr	Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate
title_full_unstemmed	Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate
title_sort	using patient-derived ipscs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/ca6c14c5e42546afa52dabe821a5a19d
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Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate

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