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; Xiaojin Wu

doi:10.18632/oncotarget.22141

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

Oncotarget. 2017 Oct 27;8(60):102088-102096. doi: 10.18632/oncotarget.22141. eCollection 2017 Nov 24.

Authors

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 Yu⁶, Depei Wu^{1

2

3

4}, Xiaojin Wu^{1

2

3

4}

Affiliations

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.

^# Contributed equally.

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.

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