Upregulation of Tim-3 is associated with poor prognosis in acute myeloid leukemia.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy originated from leukemia stem cells (LSC). Emerging evidence suggests T-cell immunoglobulin mucin-3(Tim3) as surface marker for LSC. However, the clinical significance and biology of Tim-3 in AML remain to be determined, especially those LSCs. In public AML databases as well as our data, we separated AML patients into Tim-3high and Tim-3low subsets using the X-tile software and evaluated the associations between Tim-3 and overall survival (OS) and disease-free survival (DFS). The Cancer Genome Atlas (TCGA) cohort revealed that high Tim-3 expression in leukemic cells was linked with poor prognosis (DFS: p=0.018; OS: p=0.041). Furthermore, multiple regression analysis shows that Tim-3 was an independent factor for the prognosis (HR=2.26, 95% CI=1.15-4.44, p=0.017). Validation cohort of public gene expression omnibus (GEO) confirmed that Tim-3 was a prognostic candidate in AML. Besides, in our internal cohort, we also confirmed that over expression of Tim-3 protein in LSC/LPC made poor prognosis in AML. Additionally, we revealed that the LSC markers AKR1C3, CD34, and MMRN1 were upregulated in the Tim-3high group of TCGA. We found that the upregulated genes in the Tim-3high group were mainly enriched in immune response, cytokine binding and cell adhesion molecules, and JAK-STAT signaling pathway, by gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Collectively, we revealed that, for the first time, upregulation of Tim-3 in LSCs at the level of gene and protein expression is associated with poor prognosis and the important biological feature of Tim-3 of LSC in AML.