ARHGAP6 EXPRESSION IS ASSOCIATED WITH MOLECULAR RISK AND IMPACTS CLINICAL OUTCOMES IN ACUTE MYELOID LEUKEMIA

Abstract

Despite the advances in the large-scale generation of genomic data from acute myeloid leukemia (AML) patients, much effort is still needed to convert these data into biological functions, which may pave avenues for the discovery of new prognostic markers and therapeutic targets. In a previous study, four cytoskeleton-related genes (ARHGAP6, EZR, MAP3K11 and PAK1) were identified as a prognostic factor in AML. In the present study, we detail the prognostic impact, as well as its functional genomic associations, of the ARHGAP6 gene in AML patients. Clinical and genomic data were obtained from the TCGA AML cohort (n = 173). The clinical impact (overall survival [OS] and disease-free survival [DFS]) for ARHGAP6 expression was investigated by the proportional hazards Cox regression model. Functional genomic analyzes were performed by gene set enrichment analysis (GSEA) and Gene Ontology (GO) from differentially expressed (DEG) genes obtained from the Galaxy tool. All p values were two sided with a significance level of 5%. ARGHAP6 expression was higher in the intermediate and high molecular risk groups in AML patients (all p < 0.01). High ARGHAP6 expression was identified as an independent risk factor for OS (HR = 1.92; p = 0.001) and DFS (HR = 1.96; p = 0.01) when analyzed with confounders, age, gender, white blood cell count, and molecular risk. In the GSEA, a total of 30 cellular and molecular events were found to be positively enriched in high ARHGAP6-expressing AML patients, which we highlighted the signaling pathways: IL6/JAK2/STAT3 (NES: 1.62; p < 0.001), NOTCH (NES: 1.60; p < 0.001), KRAS (NES: 1.59; p < 0.001), IL2/STAT5 (NES: 1.51; p < 0.001), TGF BETA (NES: 1.39; p = 0.03) and BETA CATENIN SIGNALING (NES: 1.36; p = 0.04). In GO analyses, high ARHGAP6 expression was associated with important processes for cancer development and progression such as cell signaling mediated by surface receptors, signal transduction, linkage to growth factors, and regulation of cell population proliferation (all p < 0.001). ARHGAP6 is a RhoGAP that acts converting RhoGTPases in its inactive GDP-bound state, which may regulate the interactions of signaling molecules with the actin cytoskeleton. It promotes continuous elongation of cytoplasmic processes during cell motility and simultaneous retraction of the cell body changing the cell morphology. The role of ARHGAP6 is still poorly established in cancer, but it is known to modulate pathways of RhoGTPases. In this sense, our study is a pioneer in the identification of this gene in processes related to neoplastic hematopoiesis, which will guide future investigations. ARHGAP6 gene expression was identified as an independent marker of poor prognosis in AML patients. The GSEA suggested that high ARHGAP6 expression is associated with activation of relevant processes to the malignant phenotype of AML. FAPESP, CNPq and CAPES.