Oncotarget

Research Papers:

High Tim-3 expression on AML blasts could enhance chemotherapy sensitivity

Liangjing Xu, Jinge Xu, Shoubao Ma, Xiaoli Li, Mingqing Zhu, Suning Chen, Yue Han, Xiaowen Tang, Zhengzheng Fu, Huiying Qiu, Jianhua Yu, Depei Wu _ and Xiaojin Wu

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Oncotarget. 2017; 8:102088-102096. https://doi.org/10.18632/oncotarget.22141

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Abstract

Liangjing Xu1,2,3,4,*, Jinge Xu1,2,3,4,5,*, Shoubao Ma2,3,4,*, Xiaoli Li1,2,3,4, Mingqing Zhu1,2,3,4, Suning Chen1,2,3,4, Yue Han1,2,3,4, Xiaowen Tang1,2,3,4, Zhengzheng Fu1,2,3,4, Huiying Qiu1,2,3,4, Jianhua Yu6, Depei Wu1,2,3,4 and Xiaojin Wu1,2,3,4

1Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China

2Institute of Blood and Marrow Transplantation, Suzhou, China

3Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

4Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China

5The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China

6The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA

*These authors contributed equally to this work

Correspondence to:

Depei Wu, email: wudepei@medmail.com.cn

Jianhua Yu, email: Jianhua.yu@osumc.edu

Xiaojin Wu, email: wuxiaojin@suda.edu.cn

Keywords: Tim-3; acute leukemia; expression; chemotherapy

Received: June 14, 2017     Accepted: August 17, 2017     Published: October 27, 2017

ABSTRACT

T-cell immunoglobulin and mucin domain-containing molecule3 (Tim-3) represents a novel mechanism of T-cell dysfunction and exhaustion. Tim-3 has also been identified in various solid tumors. However, the role of Tim-3 expression on blast cells in acute myeloid leukemia (AML) is not well understood. In this study, we aimed to explore the role of Tim-3 in patients with de novo AML, and the correlation between Tim-3 and clinicopathological prognosis. The study cohort consisted of 76 patients with de novo non-M3 AML. These patients’ bone marrow samples were collected and then bone marrow mononuclear cells (BMCs) were isolated for flow cytometry to detect Tim-3 expression on blasts. According to FAB type, 76 diagnosed AML patients included in this study were: M0 (n=2), M1 (n=16), M2 (n=20), M4 (n=20), M5 (n=16), and M6 (n=2). A positive expression (>20%) of Tim-3 was found in 87% (66/76) of patients with AML. The average percentage of Tim-3(+) blasts in these AML patients was 58.26 ± 29.23%. Moreover, the frequency of Tim-3 high expression was higher in M4 patients than that in other AML patients according to FAB type (P=0.004). Tim-3 high expression was also closely associated with inv(16) (P=0.01) and C/EBPA mutation (P=0.03). The mutations of the following six genes, i.e., FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, were independent of the Tim-3 expression. Additionally, it is more likely to find higher levels of Tim-3 in the low-risk group than in the intermediate- and high-risk groups (P=0.02). The expression of Tim-3 was positively correlated with CD13 (r=0.36, P=0.001), CD34 (r=0.41, P=0.000), and CD7 (r=0.27, P=0.02) in AML patients. AML patients with high Tim-3 expression achieved significantly high complete remission (CR) rate (P=0.01), while their Tim-3 expression significantly decreased after CR (P=0.01). Blockade of Tim-3 expression on AML blasts significantly reduced the Idarubicin (IDA)-mediated suppression of cell growth and reduction of cell apoptosis in vitro. Collectively, our study suggests that high Tim-3 expression on AML blasts could enhances chemotherapy sensitivity.


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