Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate.
Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate.
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DOI：
10.1038/s41598-018-34193-1
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发表时间：
2018-10-26
影响因子：
4.6
通讯作者：
Kurokawa M
中科院分区：
文献类型：
--
作者：
Taoka K;Arai S;Kataoka K;Hosoi M;Miyauchi M;Yamazaki S;Honda A;Aixinjueluo W;Kobayashi T;Kumano K;Yoshimi A;Otsu M;Niwa A;Nakahata T;Nakauchi H;Kurokawa M
慢性粒单核细胞白血病(CMML)是一种骨髓增生异常综合征/骨髓增生性肿瘤。虽然CMML可以通过异基因干细胞移植治愈，但由于化疗效果有限以及患者的年龄，通常不适合移植，其预后通常很差。由于CMML缺乏细胞系和小鼠模型的发展，对CMML病理生理的全面分析和治疗药物的开发一直受到限制。在成功地建立了CMML患者来源的疾病特异性诱导多能干细胞(IPSCs)后，我们利用这些CMML-IPSCs在体外实现了造血再分化，通过畸胎瘤建立了人源化的CMML小鼠模型，并开发了药物检测系统。通过体外造血再分化和体内人源化的CMML小鼠模型，总结了CMML的临床特征。使用CMML-IPSCs的药物测试系统确定MEK抑制剂、RAS抑制剂和脂质体克罗膦酸盐是治疗CMML的潜在药物。氯屈膦酸盐是一种常用的治疗骨质疏松症的双磷酸盐药物。在这项研究中，氯屈膦酸盐的脂质化增强了它在这些检测中的有效性，这表明这种变化的氯屈膦酸盐可能被用作CMML治疗的重新定位药物。
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.
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影响因子：
82.9
作者：
Seiler M;Yoshimi A;Darman R;Chan B;Keaney G;Thomas M;Agrawal AA;Caleb B;Csibi A;Sean E;Fekkes P;Karr C;Klimek V;Lai G;Lee L;Kumar P;Lee SC;Liu X;Mackenzie C;Meeske C;Mizui Y;Padron E;Park E;Pazolli E;Peng S;Prajapati S;Taylor J;Teng T;Wang J;Warmuth M;Yao H;Yu L;Zhu P;Abdel-Wahab O;Smith PG;Buonamici S
通讯作者：
Buonamici S
影响因子：
46.9
作者：
Deng, Jie;Shoemaker, Robert;Xie, Bin;Gore, Athurva;LeProust, Emily M.;Antosiewicz-Bourget, Jessica;Egli, Dieter;Maherali, Nimet;Park, In-Hyun;Yu, Junying;Daley, George Q.;Eggan, Kevin;Hochedlinger, Konrad;Thomson, James;Wang, Wei;Gao, Yuan;Zhang, Kun
通讯作者：
Zhang, Kun
影响因子：
23.9
作者：
Kotini, Andriana G.;Chang, Chan-Jung;Papapetrou, Eirini P.
通讯作者：
Papapetrou, Eirini P.
影响因子：
7.5
作者：
Zhang, Yanyan;He, Liang;Louache, Fawzia
通讯作者：
Louache, Fawzia
影响因子：
20.3
作者：
Padron, Eric;Painter, Jeffrey S.;Epling-Burnette, Pearlie K.
通讯作者：
Epling-Burnette, Pearlie K.