Tim-3 Mutation Might Play in the Pathophysiology of Acute Myeloid Leukemia

Genetic polymorphisms and expression of T-cell immunoglobulin mucin-3 (Tim-3) were associated with susceptibility and prognosis in some tumors, but the relationship between Tim-3 mutation and acute myeloid leukemia (AML) was rarely reported. This study explored the effects of Tim-3 mutations on AML. Four hundred and ninety-one de novo newly diagnosed AML patients were enrolled in this exploratory study. A genomic panel of 167 gene targets were detected by next-generation sequencing (NGS). A matched-pair analysis was designed for prognosis based on 1:2 ratio. 26 patients carried Tim-3 mutations, including 20 Tim-3 p.Y82C and other 6 mutations of p.E273K, p.E182N190del, p.Ter302E, p.A28V, p.R184W, p.G54fs. The median number of somatic mutations apart from Tim-3 was 6 and 7 in Tim-3 ⁺ and Tim-3 ^- groups (P=0.543), respectively. Tim-3 expression was lower, and white blood cell (WBC) at diagnose was higher (P=0.045) in Tim-3 ⁺ than Tim-3 ^- groups. The 2-year cumulative incidence of relapse was 50.8% and 28.7% (P=0.043), overall survival (OS) was 42.6% and 68.5% (P=0.048), and event-free survival (EFS) was 26.8% and 49.6% (P=0.028) in both groups, respectively. Multivariate analysis showed that WBC at diagnose was the risk factor (P=0.004, 0.011 and 0.000, respectively) while transplantation was the protective factor (P=0.015，0.000 and 0.000) for relapse, OS and EFS, and Tim-3 mutation was the risk factor for relapse (P=0.006) in the normal karyotype patients. In vitro, AML cell lines with Tim-3 p.Y82C overexpression revealed lower Tim-3 expression and apoptotic rate as well as lower sensitivity to cytarabine. The bioinformatic analysis also indicated Tim-3 low expression was associated with lower survival in AML patients (P=0.0009). Our findings provide new viewpoint that Tim-3 mutation results in Tim-3 lower expression and is a poor prognostic factor in AML.