THE GENOMIC LANDSCAPE OF THE SWITCH/SUCROSE NON-FERMENTABLE CHROMATIN REMODELING COMPLEX IN ACUTE MYLEOID LEUKEMIA

Abstract

The SWI/SNF chromatin remodeling complex is involved in the regulation of gene expression required for processes such as cell maintenance and differentiation in hematopoietic stem cells. Abnormalities in the SWI/SNF subunits involved in the homeostasis of hematologic processes contribute to the initiation or progression of hematologic malignancies, but the mechanisms underlying this phenotype are not yet fully understood. The aim of study is to comprehensively identify mutations and expression profiles in the genes forming the SWI/SNF complex using bioinformatics tools, with a focus on understanding the underlying mechanisms. Genomic sequences and expression profiles of an AML cohort (n:872) were obtained from using tools and subsequently analyzed. PolyPhen-2, SIFT, and Mutation Assessor tools were used to estimate the oncogenic/pathogenic effects of mutations identified in 9 genes encoding subunits of the complex ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCE1, SMARCB1, DPF2, PMBR1, and BCL7A in AML pathogenesis. STRING analysis was performed to better understand the functional relationships of the mutant proteins in cellular processes. Furthermore, to the mutation profile, gene expression and survival profiles were also determined. A total of 17 genetic abnormalities were determined in 9 genes, including 9 missense, 6 frameshift mutations, 1 mutation in the splice region, and 1 fusion mutation. In the AML cohort, the expression levels of ARID1A, ARID1B, SMARCA2, and PMBR1 were significantly higher in the patient group compared to the healthy group (p<0.01). Survival analysis based on low and high gene expression profiles showed no significant difference in results. In STRING analysis, our genes were found to have functional relationships with the PHF10 protein, which is involved in cell cycle control. The results suggest that the mutations identified in the ARID1A, ARID1B, SMARCA2, SMARCA4, and PBRM1 may disrupt the function of SWI/SNF chromatin remodeling complexes, possibly inducing/activating different cellular pathways involving different chromatin environments during AML pathogenesis.