SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes.
SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes.
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DOI：
10.1371/journal.pone.0018372
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发表时间：
2011-04-19
期刊：
影响因子：
3.7
通讯作者：
Chai L
中科院分区：
文献类型：
--
作者：
Jeong HW;Cui W;Yang Y;Lu J;He J;Li A;Song D;Guo Y;Liu BH;Chai L
我们之前的工作表明，干细胞因子SALL4在胚胎干细胞和白血病干细胞中发挥着核心作用。在这项研究中，我们报告了SALL4在耐药的原发急性髓系白血病患者中的表达高于药物敏感的患者。此外，尽管SALL4过表达导致细胞耐药，但SALL4表达降低的细胞比亲本细胞对药物更敏感。这使得我们研究了SALL4在耐药中的意义以及它在副群体(SP)癌症干细胞中的作用。在各种恶性血液病细胞系中，SP细胞的SALL4表达比非SP细胞高2-4倍。在分离的SP细胞中敲除SALL4导致SP细胞减少，表明SALL4是SP细胞自我更新所必需的。已知的SP表型是由三磷酸腺苷结合盒(ABC)药物转运蛋白家族的成员如ABCG2和ABCA3介导的。通过染色质免疫沉淀(ChIP)、定量逆转录聚合酶链式反应(qRT-PCR)和凝胶迁移率改变分析(EMSA)，我们证明SALL4能够与ABCA3启动子区域结合并激活其表达，同时间接调节ABCG2的表达。原发白血病患者SALL4的表达与ABCG2、ABCA3的表达呈正相关。综上所述，我们的结果提示SALL4在药物敏感性中的一个新的作用，至少部分是通过维持SP细胞，因此可能是白血病耐药的原因。我们首次证明干细胞因子SALL4、SP与白血病耐药之间存在直接联系。
Our previous work shows that the stem cell factor SALL4 plays a central role in embryonic and leukemic stem cells. In this study, we report that SALL4 expression was higher in drug resistant primary acute myeloid leukemic patients than those from drug-responsive cases. In addition, while overexpression of SALL4 led to drug resistance in cell lines, cells with decreased SALL4 expression were more sensitive to drug treatments than the parental cells. This led to our investigation of the implication of SALL4 in drug resistance and its role in side population (SP) cancer stem cells. SALL4 expression was higher in SP cells compared to non-SP cells by 2–4 fold in various malignant hematopoietic cell lines. Knocking down of SALL4 in isolated SP cells resulted in a reduction of SP cells, indicating that SALL4 is required for their self-renewal. The SP phenotype is known to be mediated by members of the ATP-binding cassette (ABC) drug transport protein family, such as ABCG2 and ABCA3. Using chromatin-immunoprecipitation (ChIP), quantitative reverse transcription polymerase chain reaction (qRT-PCR) and electrophoretic mobility shift assay(EMSA), we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. Furthermore, SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples. Taken together, our results suggest a novel role for SALL4 in drug sensitivity, at least in part through the maintenance of SP cells, and therefore may be responsible for drug-resistance in leukemia. We are the first to demonstrate a direct link between stem cell factor SALL4, SP and drug resistance in leukemia.
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