Favorable clinical outcome and unique characteristics in association with Twist1 overexpression in de novo acute myeloid leukemia.

C-C Chen,C-E Huang,J-Y You,J-P Gau,Y-Y Chen,J Lung,M-H Yang,H-J Chou,Y-H Tsai

doi:10.1038/bcj.2015.67

Abstract

Epithelial–mesenchymal transition (EMT) is a critical process for inducing stem-like properties of epithelial cancer cells. However, the role of EMT inducers in hematological malignancies is unknown. Twist1, an EMT inducer necessary for cell migration, has recently been found to have transcriptionally regulatory activity on the expression of Bmi1, and these two are capable of promoting tumorigenesis in a synergized manner. Knowing that Bmi1 expression is essential for maintenance of leukemic stem cells, we speculate that Twist1 might govern the pathogenesis of acute myeloid leukemia (AML) development as well. We found that upregulated Twist1 increased Bmi1 expression in AML and endued leukemic cells a higher proliferative potential and increased resistance to apoptosis. In primary AML samples, there was strong positive correlation between the expression levels of Twist1 and Bmi1. AML patients whose leukemic blasts harbored overexpressed Twist1 had a more aggressive clinical phenotype, but they were more likely to have a better clinical outcome after standard therapy. In vitro studies confirmed that Twist1-overexpressing leukemic cells were more susceptible to cytarabine, but not daunorubicin, cytotoxicity. Our findings suggest that, in a subset of AML patients, Twist1 has a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

Highlights

Acute myeloid leukemia (AML) is a clonal hematological disease characterized by multiple genetic anomalies resulting in altered self renewal, impaired cell differentiation, excessive proliferation and inadequate apoptosis.[1]
By taking a closer look, we found that the pretreatment platelet count was lower, whereas the percentage of blasts in peripheral blood (PB) as well as the serum lactate dehydrogenase (LDH) level was higher in Twist1-overexpressed patients, the differences between these two groups were not statistically significant
Twist[1] has been implicated in several molecular pathways that are engaged in tumor progression, apoptosis and Epithelial–mesenchymal transition (EMT).[27,28,29,30,31]

Summary

Introduction

Acute myeloid leukemia (AML) is a clonal hematological disease characterized by multiple genetic anomalies resulting in altered self renewal, impaired cell differentiation, excessive proliferation and inadequate apoptosis.[1]. Recent advances in molecular biology have led to identification of several genetic markers with important prognostic implication in AML, such as mutations in FLT3 (fms-like tyrosine kinase 3),[2] NPM1 (nucleophosmin 1)[3] and CEBPA (CCAAT/enhancer binding protein alpha).[4] These markers are adequately incorporated in clinical guidelines to predict outcome and direct therapy in AML.[5,6]. A large number of AML patients do not possess these predictive markers and there remains significant discrepancy in the clinical outcome of patients within the same categorized risk group.[7] there is a pressing urgency that additional biomarkers with novel pathognomic indication and accurate prognostic value are needed for further refinement of AML risk categorization

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