Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Cancer Med. 2023 Apr;12(7):8956-8969. doi: 10.1002/cam4.5549. Epub 2022 Dec 21.
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-3 and Tim-3 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-3 group of TCGA. We found that the upregulated genes in the Tim-3 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.
急性髓系白血病 (AML) 是一种起源于白血病干细胞 (LSC) 的异质性造血恶性肿瘤。新出现的证据表明 T 细胞免疫球蛋白粘蛋白-3（Tim3）是 LSC 的表面标志物。然而，Tim-3 在 AML 中的临床意义和生物学特性仍有待确定，尤其是那些 LSCs。在公共 AML 数据库以及我们的数据中，我们使用 X-tile 软件将 AML 患者分为 Tim-3 和 Tim-3 亚组，并评估了 Tim-3 与总生存期（OS）和无病生存期（DFS）之间的相关性。癌症基因组图谱 (TCGA) 队列表明，白血病细胞中高表达 Tim-3 与预后不良相关（DFS：p=0.018；OS：p=0.041）。此外，多因素回归分析表明，Tim-3 是预后的独立因素（HR=2.26，95%CI=1.15-4.44，p=0.017）。公共基因表达综合数据库 (GEO) 的验证队列证实，Tim-3 是 AML 的预后候选基因。此外，在我们的内部队列中，我们还证实 LSC/LPC 中 Tim-3 蛋白的过度表达与 AML 的不良预后有关。此外，我们还揭示了在 TCGA 中 Tim-3 组中 LSC 标志物 AKR1C3、CD34 和 MMRN1 上调。通过基因本体 (GO) 富集分析和京都基因与基因组百科全书 (KEGG) 分析，我们发现 Tim-3 组中上调的基因主要富集在免疫反应、细胞因子结合和细胞粘附分子以及 JAK-STAT 信号通路中。总之，我们首次揭示了 LSCs 中 Tim-3 基因和蛋白表达水平的上调与预后不良相关，以及 Tim-3 在 AML 中 LSC 的重要生物学特征。
