Format

Send to

Choose Destination
Sci Rep. 2018 Oct 26;8(1):15855. doi: 10.1038/s41598-018-34193-1.

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

Author information

1
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
2
CREST, Japan Science and Technology Agency (JST), 5-7 Chiyoda-ku, Tokyo, 102-0076, Japan.
3
Department of Pathology and Tumor Biology, Kyoto University, Kyoto University, 53 Kawahara-cho, Yoshidakonoecho, Sakyo-ku, Kyoto, 606-8315, Japan.
4
Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
5
Division of Stem Cell Processing/Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shiroganedai, Minatoku, Tokyo, 102-8639, Japan.
6
Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
7
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shiroganedai, Minatoku, Tokyo, 102-8639, Japan.
8
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. kurokawa-tky@umin.ac.jp.
9
CREST, Japan Science and Technology Agency (JST), 5-7 Chiyoda-ku, Tokyo, 102-0076, Japan. kurokawa-tky@umin.ac.jp.

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.

PMID:
30367142
PMCID:
PMC6203784
DOI:
10.1038/s41598-018-34193-1
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center