Identification of STAB1 in Multiple Datasets as a Prognostic Factor for Cytogenetically Normal AML: Mechanism and Drug Indications

Abstract

Cytogenetically normal acute myeloid leukemia (CN-AML) presents with diverse outcomes in different patients and is categorized as an intermediate prognosis group. It is important to identify prognostic factors for CN-AML risk stratification. In this study, using the TCGA CN-AML dataset, we found that the scavenger receptor stabilin-1 (STAB1) is a prognostic factor for poor outcomes and validated it in three other independent CN-AML datasets. The high STAB1 expression (STAB1^high) group had shorter event-free survival compared with the low STAB1 expression (STAB1^low) group in both the TCGA dataset (n = 79; p = 0.0478) and GEO: GSE6891 dataset (n = 187; p = 0.0354). Differential expression analysis between the STAB1^high and STAB1^low groups revealed that upregulated genes in the STAB1^high group were enriched in pathways related to cell adhesion and migration and immune responses. We confirmed that STAB1 suppression inhibits cell growth in KG1a and NB4 leukemia cells. Expression correlation analyses between STAB1 and cancer drug targets suggested that patients in the STAB1^low group are more sensitive to the BCL2 inhibitor venetoclax, and we confirmed it in cell lines. In conclusion, we identified STAB1 as a prognostic factor for CN-AML in multiple datasets, explored its underlying mechanism, and provided potential therapeutic indications.

Keywords: STAB1; cytogenetically normal acute myeloid leukemia; prognostic factor; therapeutic indications.

Figure 1

Selection of STAB1 as a Prognostic Factor for CN-AML (A) Heatmap of differentially expressed genes associated with OS in the TCGA dataset. (B) OS analysis of STAB1 in five CN-AML datasets. (C) EFS correlation of STAB1 in CN-AML in the TCGA and GSE6891 datasets.

Figure 2

miRNA-TF Regulation and Its Correlation with STAB1 (A) Enriched GO/KEGG terms of differential genes in the STAB1^high versus STAB1^l°^w groups. Numbers in brackets are the numbers of differential genes in each category. The enrich ratio represents the proportion of enriched genes accounting for the terms. (B) The miRNA-TF co-regulatory network for the enriched terms in (A). Triangles, TFs; circles, target genes; rounded rectangles, miRNAs; red nodes, upregulation in the STAB1^high group; green nodes, downregulation.

Figure 3

Expression Correlation of STAB1 and Drug Targets in the STAB1^high and STAB1^low Groups (A) Correlation of STAB1 expression with gene targets of leukemia drugs. Hexagons, STAB1. (B) Correlation of STAB1 expression with gene targets of FDA-approved cancer drugs. Circles, targeted genes; arrowheads, drugs. The red nodes represent genes resistant to drugs in the STAB1^high group; the green nodes represent genes sensitive to drugs in the STAB1^high group. The colors of the edges represent different expression correlations (red, positive; blue, negative) between STAB1 and the drug targets. The size of the circle nodes represents the correlation strength between STAB1 and the target genes.

Figure 4

STAB1 Suppression Inhibits Leukemic Cell Growth and Shows More Sensitivity to Venetoclax in KG1a and NB4 Cells (A) Relative mRNA expression level (after log2 conversion) of STAB1 in six hematological cell lines analyzed by real-time qPCR. (B) Relative mRNA expression fold change of KG1a cells transfected with NC and three STAB1-specific siRNAs for 48 h. (C) Western blot analysis of KG1a and NB4 cells transfected with si-STAB1-2. (D) Cell proliferation of KG1a and NB4 cells transfected with NC or si-STAB1 for 72 h tested using the CCK8 assay. (E) Cell proliferation graph of KG1a cells and NB4 cells transfected with NC or si-STAB1 treated with venetoclax and tested using the CCK8 assay. Each experiment was repeated at least three times. Error bars represent SD.