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

Abstract

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.

Keywords

• acute myeloid leukemia
• immune response
• leukemia stem cell
• prognosis
• T‐cell immunoglobulin mucin 3