ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis: Targeting It Eradicates Leukemia Stem Cells
ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis: Targeting It Eradicates Leukemia Stem Cells
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ORP4L 从质膜中提取并呈现 PIP2 用于 PLC beta 3 催化：靶向它根除白血病干细胞
DOI：
10.1016/j.celrep.2019.01.082
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发表时间：
2019
期刊：
影响因子：
8.8
通讯作者：
Yan Daoguang
中科院分区：
文献类型：
--
作者：
Zhong Wenbin;Xu Mengyang;Li Chanjuan;Zhu Biying;Cao Xiuye;Li Dan;Chen Huanzhao;Hu Chunxiu;Li Rong;Luo Chengwei;Pan Guoping;Zhang Wenqiang;Lai Chaofeng;Wang Tong;Du Xin;Chen Hong;Xu Guowang;Olkkonen Vesa M.;Lei Pingsheng;Xu Jun;Yan Daoguang
白血病干细胞（LSC）是异常造血干细胞（HSC）的罕见亚群，其传播白血病并导致治疗中的高复发频率。对LSC存活的详细了解将有助于确定治疗方法的靶点。在这里，我们开发了一种抑制剂，LYZ-81，它以高亲和力和特异性靶向ORP 4L，并在体外和体内选择性根除LCS。ORP 4L在LSC中表达，但在正常HSC中不表达，并且对LSC生物能量学和存活至关重要。它从质膜中提取PIP 2并将其呈递给PLCβ3，使IP 3产生和随后的Ca 2+依赖性生物能量学成为可能。LYZ-81与PIP 2竞争性结合ORP 4L，阻断PIP 2水解，导致Ca 2+信号转导缺陷。结果提供了证据表明，LSCs可以通过LYZ-81抑制ORP 4L来根除，这可能作为药物开发的起点，用于消除LSCs，最终治愈白血病。
Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs' survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSsin vitroandin vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP2from the plasma membrane and presents it to PLCβ3, enabling IP3generation and subsequent Ca2+-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP2and blocks PIP2hydrolysis, resulting in defective Ca2+signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia.