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

// Liangjing Xu 1, 2, 3, 4, * , Jinge Xu 1, 2, 3, 4, 5, * , Shoubao Ma 2, 3, 4, * , Xiaoli Li 1, 2, 3, 4 , Mingqing Zhu 1, 2, 3, 4 , Suning Chen 1, 2, 3, 4 , Yue Han 1, 2, 3, 4 , Xiaowen Tang 1, 2, 3, 4 , Zhengzheng Fu 1, 2, 3, 4 , Huiying Qiu 1, 2, 3, 4 , Jianhua Yu 6 , Depei Wu 1, 2, 3, 4 and Xiaojin Wu 1, 2, 3, 4 1 Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China 2 Institute of Blood and Marrow Transplantation, Suzhou, China 3 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China 4 Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China 5 The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China 6 The 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.