Increased NFATC4 Correlates With Poor Prognosis of AML Through Recruiting Regulatory T Cells

Chong Zhao; Shaoxin Yang; Wei Lu; Jiali Liu; Yanyu Wei; Hezhou Guo; Yanjie Zhang; Jun Shi

doi:10.3389/fgene.2020.573124

Increased NFATC4 Correlates With Poor Prognosis of AML Through Recruiting Regulatory T Cells

Front Genet. 2020 Nov 27:11:573124. doi: 10.3389/fgene.2020.573124. eCollection 2020.

Authors

Chong Zhao¹, Shaoxin Yang², Wei Lu², Jiali Liu¹, Yanyu Wei², Hezhou Guo², Yanjie Zhang², Jun Shi²

Affiliations

¹ Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
² Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Despite that immune responses play important roles in acute myeloid leukemia (AML), immunotherapy is still not widely used in AML due to lack of an ideal target. Therefore, we identified key immune genes and cellular components in AML by an integrated bioinformatics analysis, trying to find potential targets for AML. Eighty-six differentially expressed immune genes (DEIGs) were identified from 751 differentially expressed genes (DEGs) between AML patients with fair prognosis and poor prognosis from the TCGA database. Among them, nine prognostic immune genes, including NCR2, NPDC1, KIR2DL4, KLC3, TWIST1, SNORD3B-1, NFATC4, XCR1, and LEFTY1, were identified by univariate Cox regression analysis. A multivariable prediction model was established based on prognostic immune genes. Kaplan-Meier survival curve analysis indicated that patients in the high-risk group had a shorter survival rate and higher mortality than those in the low-risk group (P < 0.001), indicating good effectiveness of the model. Furthermore, nuclear factors of activated T cells-4 (NFATC4) was recognized as the key immune gene identified by co-expression of differentially expressed transcription factors (DETFs) and prognostic immune genes. ATP-binding cassette transporters (ABC transporters) were the downstream KEGG pathway of NFATC4, identified by gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA). To explore the immune responses NFATC4 was involved in, an immune gene set of T cell co-stimulation was identified by single-cell GSEA (ssGSEA) and Pearson correlation analysis, positively associated with NFATC4 in AML (R = 0.323, P < 0.001, positive). In order to find out the immune cell types affected by NFATC4, the CIBERSORT algorithm and Pearson correlation analysis were applied, and it was revealed that regulatory T cells (Tregs) have the highest correlation with NFATC4 (R = 0.526, P < 0.001, positive) in AML from 22 subsets of tumor-infiltrating immune cells. The results of this study were supported by multi-omics database validation. In all, our study indicated that NFATC4 was the key immune gene in AML poor prognosis through recruiting Tregs, suggesting that NFATC4 might serve as a new therapy target for AML.

Keywords: NFATc4; acute myeloid leukemia; immune response; prognosis; regulatory T cells.