Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells.
Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells.
复制标题
DOI：
10.1111/cas.13019
复制
发表时间：
2016-10
期刊：
影响因子：
5.7
通讯作者：
Naoe T
中科院分区：
文献类型：
--
作者：
Fukushima N;Minami Y;Kakiuchi S;Kuwatsuka Y;Hayakawa F;Jamieson C;Kiyoi H;Naoe T
Hedgehog信号通路的异常激活与几种模型系统中白血病干细胞群的维持有关。PF-04449913（PF-913）是Smoothened的选择性小分子抑制剂，Smoothened是一种调节Hedgehog通路的膜蛋白。然而，PF-913在急性髓性白血病（AML）患者中给药后的概念验证和作用机制的细节尚不清楚。本研究检查了Hedgehog信号通路在AML细胞中的作用，并评价了Smoothened抑制剂PF-913的体外和体内作用。在原代AML细胞中，Hedgehog信号通路的激活在CD 34+细胞中比在CD 34 −细胞中更明显。PF-913体外处理诱导静止细胞群减少，伴有极轻微的细胞死亡。在连续移植小鼠模型中，PF-913体内给药减弱了AML细胞的白血病引发潜力，同时限制了原发性异种移植系统中肿瘤负荷的降低。综合基因集富集分析显示，PF-913调节自我更新特征和细胞周期进程。此外，PF-913使AML细胞对阿糖胞苷敏感，并消除了与HS-5基质细胞共培养的AML细胞对阿糖胞苷的耐药性。这些发现意味着Hedgehog信号传导的药理学抑制减弱了白血病启动潜力，并且还通过使休眠的白血病干细胞对化疗敏感并克服骨髓微环境中的抗性来增强AML治疗。
Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF‐04449913 (PF‐913) is a selective, small‐molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof‐of‐concept and mechanism of action of PF‐913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF‐913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34+ cells than CD34− cells. In vitro treatment with PF‐913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF‐913 attenuated the leukemia‐initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF‐913 modulated self‐renewal signatures and cell cycle progression. Furthermore, PF‐913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS‐5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia‐initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-14-0507
发表时间：
2015-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Justilien V;Fields AP
通讯作者：
Fields AP
影响因子：
17.1
作者：
Lim Y;Gondek L;Li L;Wang Q;Ma H;Chang E;Huso DL;Foerster S;Marchionni L;McGovern K;Watkins DN;Peacock CD;Levis M;Smith BD;Merchant AA;Small D;Matsui W
通讯作者：
Matsui W
影响因子：
20.3
作者：
Blotta, Simona;Jakubikova, Jana;Munshi, Nikhil C.
通讯作者：
Munshi, Nikhil C.
影响因子：
12.8
作者：
Kuwatsuka, Y.;Minami, M.;Minami, Y.;Sugimoto, K.;Hayakawa, F.;Miyata, Y.;Abe, A.;Goff, D. J.;Kiyoi, H.;Naoe, T.
通讯作者：
Naoe, T.
影响因子：
5.2
作者：
Graham, Susan M.;Vass, J. Keith;Graham, Gerard J.
通讯作者：
Graham, Gerard J.