Targeting Gill Suppresses Cell Growth and Enhances Chemosensitivity in CD34+ Enriched Acute Myeloid Leukemia Progenitor Cells
Targeting Gill Suppresses Cell Growth and Enhances Chemosensitivity in CD34+ Enriched Acute Myeloid Leukemia Progenitor Cells
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DOI：
10.1159/000443075
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发表时间：
2016-01-01
影响因子：
--
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
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作者：
Long, Bing;Wang, Le-Xun;Liu, Quentin
背景/目的：急性髓系白血病（AML）患者的白血病干细胞（LSC）对化疗的耐药性导致疾病复发。Hedgehog（Hh）信号传导在癌症干细胞的维持和分化中发挥着关键作用。然而，它在AML中的作用仍然存在争议。本研究的目的是研究Hh信号转录激活因子GLI 1在AML祖细胞中的作用，并探讨GLI 61小分子抑制剂GANT 61的抗AML作用。方法：检测AML祖细胞和正常细胞中GLI 1 mRNA和蛋白的表达。还分析了在GANT 61存在下AML祖细胞的增殖、集落形成、凋亡和分化。结果如下：Kasumi-1和KG 1a细胞中含有较多的CD 34（+）细胞，其Gill表达水平高于含有较少CD 34（+）细胞的U937和NB 4细胞。一致地，在所测试的AML患者的骨髓单个核细胞（BMMC）中验证了GLI 1和CD 34的蛋白水平之间的正相关性。GANT 61抑制AML细胞系的增殖和集落形成。重要的是，GANT 61在富含CD 34（+）的Kasumi-1和KG 1a细胞中诱导凋亡，而在U937和NB 4细胞中诱导分化。此外。GANT 61增强阿糖胞苷（Ara-c）对原代CD 34（+）AML细胞的细胞毒性，表明抑制GM可能是一种有希望的增强化疗敏感性的策略。结论：Hh信号在AML祖细胞中被激活。GLI 1是AML治疗的潜在靶点。版权所有（C）2016 S. Karger AG，巴塞尔
Background/Aims: Resistance of leukemia stem cells (LSCs) to chemotherapy in patients with acute myeloid leukemia (AML) causes relapse of disease. Hedgehog (Hh) signaling plays a critical role in the maintenance and differentiation of cancer stem cells. Yet its role in AML remains controversial. The purpose of the present study is to investigate the role of GLI1, the transcriptional activator of Hh signaling, in AML progenitor cells and to explore the anti-AML effects of GLI small-molecule inhibitor GANT61. Methods: The expression of GLI1 mRNA and protein were examined in AML progenitor cells and normal cells. The proliferation, colony formation, apoptosis and differentiation of AML progenitor cells were also analyzed in the presence of GANT61. Results: Kasumi-1 and KG1a cells, containing more CD34(+) cells, expressed higher level of Gill compared to U937 and NB4 cells with fewer CD34(+) cells. Consistently, a positive correlation between the protein levels of GLI1 and CD34 was validated in the bone marrow mononuclear cells (BMMC) of AML patients tested. GANT61 inhibited the proliferation and colony formation in AML cell lines. Importantly, GANT61 induced apoptosis in CD34(+) enriched Kasumi-1 and KG1a cells, whereas it induced differentiation in U937 and NB4 cells. Furthermore. GANT61 enhanced the cytotoxicity of cytarabine (Ara-c) in primary CD34(+) AML cells, indicating that inhibition of GM could be a promising strategy to enhance chemosensitivity. Conclusions: The present findings suggested that Hh signaling was activated in AML progenitor cells. GLI1 acted as a potential target for AML therapy. Copyright (C) 2016 S. Karger AG, Basel