Identification of survival-related alternative splicing signatures in acute myeloid leukemia.

Biyu Zhang,Lei Yang,Xin Wang,Denggang Fu

doi:10.1042/bsr20204037

Abstract

Aberrant RNA alternative splicing (AS) variants play critical roles in tumorigenesis and prognosis in human cancers. Here, we conducted a comprehensive profiling of aberrant AS events in acute myeloid leukemia (AML). RNA AS profile, including seven AS types, and the percent spliced in (PSI) value for each patient were generated by SpliceSeq using RNA-seq data from TCGA. Univariate followed by multivariate Cox regression analysis were used to identify survival-related AS events and develop the AS signatures. A nomogram was developed, and its predictive efficacy was assessed. About 27,892 AS events and 3,178 events were associated with overall survival (OS) after strict filtering. Parent genes of survival-associated AS events were mainly enriched in leukemia-associated processes including chromatin modification, autophagy, and T-cell receptor signaling pathway. The 10 AS signature based on seven types of AS events showed better efficacy in predicting OS of patients than those built on a single AS event type. The area under curve (AUC) value of the 10 AS signature for 3-year OS was 0.91. Gene set enrichment analysis (GSEA) confirmed that these survival-related AS events contribute to AML progression. Moreover, the nomogram showed good predictive performance for patient's prognosis. Finally, the correlation network of AS variants with splicing factor genes found potential important regulatory genes in AML. The present study presented a systematic analysis of survival-related AS events and developed AS signatures for predicting the patient’s survival. Further studies are needed to validate the signatures in independent AML cohorts and might provide a promising perspective for developing therapeutic targets.

Highlights

Acute myeloid leukemia (AML) is one of the most aggressive and heterogeneous hematologic malignancies characterized by uncontrolled clonal expansion of poorly differentiated myeloid cells [1,2]
alternative splicing (AS) events were divided into seven types including alternate acceptor site (AA), alternate donor site (AD), alternate promoter (AP), alternate terminator (AT), exon skip (ES), retained intron (RI), and mutually exclusive exons (ME) (Figure 1B)
A total of 27,892 AS events were detected in 8,338 genes, comprised 1,989 AAs in 1,493 genes, 1,567 ADs in 1,207 genes, 5,402 APs in 2,573 genes, 6,044 ATs in 2,900 genes, 9,116 ESs in 3,852 genes, 1,722 RIs in 1,110 genes, and 127 MEs in 125 genes (Figure 1C)

Summary

Introduction

Acute myeloid leukemia (AML) is one of the most aggressive and heterogeneous hematologic malignancies characterized by uncontrolled clonal expansion of poorly differentiated myeloid cells [1,2]. Various investigations have focused on developing novel therapeutics in recent years [4,5], while the overall survival (OS) of AML patients has not significantly improved in the several past decades. There is an urgent need to identify additional prognostic biomarkers and develop effective therapies to cure AML [1]. RNA alternative splicing (AS) is a critical regulatory process of gene expression post-transcription [6] that contributes to proteome diversity, and functional and phenotypic complexity by generating distinct RNA isoforms from a single gene through different arrangements, including removal of intronic regions and selective inclusion or exclusion of specific exons [7]. Alternative AS events have become a hallmark of cancer, and potential targets for developing new therapeutics [8]. Many AS events have been identified that are correlated with several cancer-related hallmarks, such as epithelial–mesenchymal transition

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Results

Conclusion