Genome-wide investigation of differentially expressed alternative splicing and RNA-binding protein genes association with AML drug resistance

Abstract Background Acute myeloid leukaemia (AML) is a malignancy of the haematopoietic system with extremely high mortality. Current AML therapies, such as chemotherapy, hematopoietic stem cell transplantation, and targeted therapy, have greatly improved the prognosis of AML patients. However, there are still a number of AML patients who develop drug resistance after pharmacotherapy, leading to poor prognosis and relapse. Currently, the global 5-year survival rate for adults with AML remains below 50%. Therefore, it is urgent to identify the aetiology for AML relapse and drug resistance. Methods Bone marrow mononuclear cells were isolated from bone marrow blood samples from 4 patients with AML relapse, 3 patients with AML remission and 5 control donors by density gradient centrifugation using Lymphocyte separation medium. After RNA extraction and sequencing, differentially expressed genes (DEGs) analysis, overlapping analysis, WGCNA and co-expression analysis, alternative splicing analysis and functional enrichment analysis were further performed. Results RNA sequencing andDEGs analysis demonstrated that a total of 593 overlapped up-regulated genes and 999 overlapped down-regulated genes were discovered in the reAML group in comparison to the Healthy and AML groups. Of particular, further overlapping analysis revealed that 33 RBP genes were overlapped up-regulated and 30 RBP genes were overlapped down-regulated in the reAML group. Further WGCNA and alternative splicing analyses highlighted that significant changes were found in AS in the reAML group compared with the AML and Healthy groups, and multiple differential regulatory alternative splicing genes (RASGs) and regulatory alternative splicing events (RASEs) were also identified. Conclusions The aberrance of regulatory alternative splicing (RAS) and differential expression of RNA-binding protein (RBP) genes are highly associated with AML relapse and drug resistance in AML patients.