Gas6/AXL Signaling Regulates Self-Renewal of Chronic Myelogenous Leukemia Stem Cells by Stabilizing β-Catenin
Gas6/AXL Signaling Regulates Self-Renewal of Chronic Myelogenous Leukemia Stem Cells by Stabilizing β-Catenin
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DOI：
10.1158/1078-0432.ccr-16-1298
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发表时间：
2017-06-01
影响因子：
11.5
通讯作者：
Pan, Jingxuan
中科院分区：
文献类型：
--
作者：
Jin, Yanli;Nie, Danian;Pan, Jingxuan
目的：静止期白血病干细胞（LSC）是慢性粒细胞白血病（CML）耐药和复发的重要来源。因此，需要根除CML LSC的策略来治愈。在本研究中，我们发现AXL酪氨酸激酶在原代CML CD 34（+）细胞中选择性过表达。实验设计：采用流式细胞仪、CFC/再铺板、长期培养起始细胞（LTC-IC）、人BCR-ABL基因驱动的CML小鼠模型和NOD-scid-IL 2 Rg（-/-）（NSI）小鼠，对CML CD 34（+）细胞的功能进行评价。AXL在原代CML CD 34（+）细胞中选择性过表达。AXL基因敲除降低了人CML CD 34（+）细胞的存活和自我更新能力。AXL的药理学抑制降低了体外和NSI小鼠长期移植物中人CML LSC的存活和自我更新能力。人CML CD 34（+）细胞募集骨髓源性基质细胞（BMDSC）和原代间充质干细胞（MSC）分泌Gas 6以形成促进LSC自我更新的旁分泌环。通过shRNA和抑制剂抑制AXL延长了CML小鼠的存活时间，并减少了小鼠LSC的生长。Gas 6/AXL连接在人CML CD 34（+）细胞中以AKT依赖的方式稳定β-连环蛋白。结论：我们的研究结果提高了对LSC调控的理解，并验证了Gas 6/AXL作为一对消除CML LSC的治疗靶点。(C)2016年AACR。
Purpose: Quiescent leukemia stem cells (LSC) are important resources of resistance and relapse in chronic myelogenous leukemia (CML). Thus, strategies eradicating CML LSCs are required for cure. In this study, we discovered that AXL tyrosine kinase was selectively overexpressed in primary CML CD34(+) cells. However, the role of AXL and its ligand Gas6 secreted by stromal cells in the regulation of self-renewal capacity of LSCs has not been well investigated.Experimental Design: The function of CML CD34(+) cells was evaluated by flow cytometer, CFC/replating, long-term culture-initiating cells (LTC-IC), CML mouse model driven by human BCR-ABL gene and NOD-scid-IL2Rg(-/-) (NSI) mice.Results: AXL was selectively overexpressed in primary CML CD34(+) cells. AXL knockdown reduced the survival and self-renewal capacity of human CML CD34(+) cells. Pharmacologic inhibition of AXL reduced the survival and self-renewal capacity of human CML LSCs in vitro and in long-term grafts in NSI mice. Human CML CD34(+) cells conscripted bone marrow-derived stromal cells (BMDSC) and primary mesenchymal stem cells (MSC) to secrete Gas6 to form a paracrine loop that promoted self-renewal of LSCs. Suppression of AXL by shRNA and inhibitor prolonged survival of CML mice and reduced the growth of LSCs in mice. Gas6/AXL ligation stabilizes beta-catenin in an AKT-dependent fashion in human CML CD34(+) cells.Conclusions: Our findings improve the understanding of LSC regulation and validate Gas6/AXL as a pair of therapeutic targets to eliminate CML LSCs. (C) 2016 AACR.