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

被引：51

作者：

Wang, Nan ^{[1
]}

Guo, Dan ^{[1
]}

Zhao, YangYang ^{[1
]}

Dong, ChengYa ^{[1
]}

Liu, XiaoYan ^{[1
]}

Yang, BinXia ^{[1
]}

Wang, ShuWei ^{[1
]}

Wang, Lin ^{[1
]}

Liu, QingGuo ^{[1
]}

Ren, Qian ^{[1
]}

Lin, YongMin ^{[1
]}

Ma, XiaoTong ^{[1
]}

机构：

[1] Chinese Acad Med Sci, Peking Union Med Coll, Inst Hematol & Blood Dis Hosp, State Key Lab Expt Hematol, Beijing, Peoples R China

来源：

ONCOTARGET | 2015年 / 6卷 / 25期

基金：

中国国家自然科学基金;

关键词：

TWIST-1; myeloid leukemia; leukemia stem cell; prognostic factor; c-MPL; CANCER STEM-CELLS; SELF-RENEWAL; C-MPL; BREAST-CANCER; THERAPEUTIC TARGET; UP-REGULATION; EXPRESSION; GENE; THROMBOPOIETIN; METASTASIS;

D O I：

10.18632/oncotarget.4007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：20977 / 20992

页数：16

共 58 条

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