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

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 AML. RNA AS profile, including 7 AS types, and the Percent Spliced In (PSI) value for each patient was 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. 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 signatures based on 7 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 patients’ prognosis. Finally, the correlation network of AS variants with splicing factor genes found potential important regulatory genes in AML. This 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 signature in independent AML cohorts and might provide a promising perspective for developing therapeutic targets.

Evaluation of the clinical significance of global mRNA alternative splicing in patients with acute myeloid leukemia

“…Recently reported large-scale RNA sequencing data analysis, based on TCGA, Beat, TARGET, and Clinseq AML cohorts investigated AS events with prognostic implications in AML patients and yielded inconsistent results, probably due to heterogeneity in the patients enrolled, treatment strategies they received, and the status of the disease when the samples were obtained. [17][18][19][20][21] Moreover, these studies lacked normal reference samples. To address these problems, our study included a large Asian AML population with a relatively homogeneous treatment regimens and incorporated normal HSC samples for reference.…”

“…However, the clinical implications of splicing aberrancy were not studied in that report. Recently reported large‐scale RNA sequencing data analysis, based on TCGA, Beat, TARGET, and Clinseq AML cohorts investigated AS events with prognostic implications in AML patients and yielded inconsistent results, probably due to heterogeneity in the patients enrolled, treatment strategies they received, and the status of the disease when the samples were obtained 17–21 . Moreover, these studies lacked normal reference samples.…”

“…11,12 Abnormal AS processes are common in benign and malignant diseases; however, their biological and clinical impacts in hematologic malignancies have not yet been extensively explored. [13][14][15][16][17][18][19][20][21][22][23] Our previous study demonstrated that the aberrancy of global AS could predict shorter overall survival (OS) and time needed for leukemic transformation in myelodysplastic neoplasm (MDS) patients. 24 Although there have been reports regarding the clinical implications of altered AS in AML patients by analyzing publicly accessible transcriptome databases, including The Cancer Genome Atlas (TCGA), Beat, Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and Clinseq_AML, [17][18][19][20][21] several issues remain unaddressed.…”

“…It is such a complex and tightly regulated process that dysregulation of this mechanism can lead to mis‐spliced transcripts, which can alter many biological functions including cell proliferation, adhesion, motility, invasion, and apoptosis 11,12 . Abnormal AS processes are common in benign and malignant diseases; however, their biological and clinical impacts in hematologic malignancies have not yet been extensively explored 13–23 . Our previous study demonstrated that the aberrancy of global AS could predict shorter overall survival (OS) and time needed for leukemic transformation in myelodysplastic neoplasm (MDS) patients 24 …”

The dual role of autophagy in acute myeloid leukemia

“…Although the evidence is inadequate, studies have supported the mediation of AML tumorigenesis by the bioinformatic tools through prediction of risk scoring based on autophagy gene signatures [ 136 , 137 ]. In addition, profiling of genome-wide alternative splicing (AS) events in the AML cohort of The Cancer Genome Atlas indicates that survival-related AS events are enriched in leukemia-associated gene sets, including the autophagy pathway [ 138 , 139 ]. Given that AS variants affect the structures and protein–protein interactions of proteins implicated in carcinogenesis [ 140 ], autophagy-related genes with aberrant AS events might be involved in AML pathogenesis.…”