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.

Nan Wang,Lin Wang,Shuwei Wang,Qingguo Liu,Xiaotong Ma,Xiaoyan Liu,Yongmin Lin,Yangyang Zhao,Binxia Yang,Qian Ren,Chengya Dong,Dan Guo

doi:10.18632/oncotarget.4007

Abstract

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.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous clonal malignancy with considerable diversity concerning clinical behavior and prognosis [1,2,3]
Our study demonstrated that TWIST-1 was highly expressed in bone marrow mononuclear cells (BMMNCs) of patients with AML and Chronic myeloid leukemia (CML), whereas normalization of TWIST-1 expression was observed in patients with acute lymphoid leukemia (ALL)
In spite of the wide range of individual values of TWIST-1, median levels of TWIST-1 were significantly higher in patients with AML and CML than in controls (n = 29), whereas no significant difference was observed in TWIST-1 expression between ALL patients and controls (Figure 1C)

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous clonal malignancy with considerable diversity concerning clinical behavior and prognosis [1,2,3]. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease characterized by constitutive activation of the BCR-ABL tyrosine kinase [4]. Despite this consistent molecular abnormality, CML still exhibits marked heterogeneity in prognosis because of development of secondary cytogenetic changes or resistance [5, 6]. Overexpression of TWIST-1 has been observed in various solid tumors and is often associated with aggressive phenotypes and poor prognosis [10,11,12,13,14]. It’s well accepted that TWIST-1, which may function as a multifunctional proto-oncogene during tumorigenesis and progression of solid tumors, protects cells from chemotherapy-induced apoptosis and senescence and promotes tumor epithelial-mesenchymal transition [13, 15,16,17,18,19]

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