Clusterization in acute myeloid leukemia based on prognostic alternative splicing signature to reveal the clinical characteristics in the bone marrow microenvironment

Nan Zhang,Shifeng Lou,Ping Zhang,Hanqing Zeng,Ying Chen,Jianchuan Deng

doi:10.1186/s13578-020-00481-5

Abstract

BackgroundAlternative splicing (AS), a crucial post-transcriptional regulatory mechanism in expanding the coding capacities of genomes and increasing the diversity of proteins, still faces various challenges in the splicing regulation mechanism of acute myeloid leukemia (AML) and microenvironmental changes.ResultsA total of 27,833 AS events were detected in 8337 genes in 178 AML patients, with exon skip being the predominant type. Approximately 11% of the AS events were significantly related to prognosis, and the prediction models based on various events demonstrated high classification efficiencies. Splicing factors correlation networks further altered the diversity of AS events through epigenetic regulation and clarified the potential mechanism of the splicing pathway. Unsupervised cluster analysis revealed significant correlations between AS and immune features, molecular mutations, immune checkpoints and clinical outcome. The results suggested that AS clusters could be used to identify patient subgroups with different survival outcomes in AML, among which C1 was both associated with good outcome in overall survival. Interestingly, C1 was associated with lower immune scores compared with C2 and C3, and favorable-risk cytogenetics was rarely distributed in C2, but much more common in C1.ConclusionsThis study revealed a comprehensive landscape of AS events, and provides new insight into molecular targeted therapy and immunotherapy strategy for AML.

Highlights

Alternative splicing (AS), a crucial post-transcriptional regulatory mechanism in expanding the coding capacities of genomes and increasing the diversity of proteins, still faces various challenges in the splicing regulation mechanism of acute myeloid leukemia (AML) and microenvironmental changes
It should be noted that several mRNA splicing events may be detected in a single gene, and up to 6 types of AS events were observable for one gene (Fig. 1c)
Based on the AS events clustering, we found that the distribution of common mutated genes was inconsistent in different clusters (Additional file 8), the mutation frequency of DNMT3A in cluster C1-C3 was 10%, Fig. 4 Correlation network of splicing factors (SFs) and the Percent Spliced In (PSI) values of survival-associated AS events in AML

Summary

Introduction

Alternative splicing (AS), a crucial post-transcriptional regulatory mechanism in expanding the coding capacities of genomes and increasing the diversity of proteins, still faces various challenges in the splicing regulation mechanism of acute myeloid leukemia (AML) and microenvironmental changes. The clinical of acute myeloid leukemia (AML) from initial diagnosis to recurrent/refractory status is characterized by the acquisition of drug resistance and progressive immune dysfunction [1]. With recent developments in generation sequencing techniques, molecular evolutionary mechanisms underlying the occurrence and clinical progression of AML are better understood, and could optimize individualized treatment [7, 8]. Alternative splicing (AS) is a crucial post-transcriptional regulatory mechanism that converts only 20,000 genes in eukaryotic cells into approximately 95,000 different proteins for generating protein diversity [9]. A good understanding of the potential function of AS could help researchers to identify new oncogenic mechanisms and therapeutic targets

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Results

Discussion

Conclusion