TWIST-1 promotes cell growth, drug resistance and progenitor clonogenic capacities in myeloid leukemia and is a novel poor prognostic factor in acute myeloid leukemia.
TWIST-1 promotes cell growth, drug resistance and progenitor clonogenic capacities in myeloid leukemia and is a novel poor prognostic factor in acute myeloid leukemia.
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TWIST-1 促进髓系白血病的细胞生长、耐药性和祖细胞克隆形成能力，是急性髓系白血病的一种新的不良预后因素。
DOI：
10.18632/oncotarget.4007
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发表时间：
2015-08-28
期刊：
影响因子：
--
通讯作者：
Ma XT
中科院分区：
文献类型：
--
作者：
Wang N;Guo D;Zhao YY;Dong CY;Liu XY;Yang BX;Wang SW;Wang L;Liu QG;Ren Q;Lin YM;Ma XT
TWIST-1表达的改变通常见于实体瘤中，并有助于肿瘤发生和癌症进展。然而，关于其在白血病中的致病作用的研究很少。我们的研究表明TWIST-1在急性髓细胞白血病（AML）和慢性髓细胞白血病（CML）患者的骨髓单个核细胞中过表达。功能获得和功能丧失分析表明TWIST-1促进AML和CML细胞系的细胞生长、集落形成和耐药性。此外，TWIST-1在CD 34 + CD 38 −白血病干细胞候选者中异常高表达，其表达随着分化而下降。髓系白血病CD 34+细胞中TWIST-1的下调损害了其集落形成能力在机制上，c-MPL在髓性白血病细胞中高度表达并与不良预后相关，被鉴定为髓性白血病患者中TWIST-1共表达的基因，并部分促成TWIST-1介导的致白血病作用。此外，在AML中，TWIST-1表达较高的患者的总体和无事件生存期（OS和EFS）较短。多变量分析进一步表明TWIST-1过表达是AML患者OS和EFS的一个新的独立不利预测因子。这些数据突出了TWIST-1作为一个新的候选基因有助于白血病的髓细胞白血病，并提出了可能的新途径，以改善AML的风险和治疗分层。
Alterations of TWIST-1 expression are often seen in solid tumors and contribute to tumorigenesis and cancer progression. However, studies concerning its pathogenic role in leukemia are scarce. Our study shows that TWIST-1 is overexpressed in bone marrow mononuclear cells of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Gain-of-function and loss-of-function analyses demonstrate that TWIST-1 promotes cell growth, colony formation and drug resistance of AML and CML cell lines. Furthermore, TWIST-1 is aberrantly highly expressed in CD34+CD38− leukemia stem cell candidates and its expression declines with differentiation. Down-modulation of TWIST-1 in myeloid leukemia CD34+ cells impairs their colony-forming capacity. Mechanistically, c-MPL, which is highly expressed in myeloid leukemia cells and associated with poor prognosis, is identified as a TWIST-1 coexpressed gene in myeloid leukemia patients and partially contributes to TWIST-1-mediated leukemogenic effects. Moreover, patients with higher TWIST-1 expression have shorter overall and event-free survival (OS and EFS) in AML. Multivariate analysis further demonstrates that TWIST-1 overexpression is a novel independent unfavourable predictor for both OS and EFS in AML. These data highlight TWIST-1 as a new candidate gene contributing to leukemogenesis of myeloid leukemia, and propose possible new avenues for improving risk and treatment stratification in AML.