Systematic Construction and Validation of an RNA-Binding Protein-Associated Prognostic Model for Acute Myeloid Leukemia.

Hongwei Luo,Yancheng He,Chengcheng He,Yingchun Zhang,Nan Hu

doi:10.3389/fgene.2021.715840

Abstract

Background: The abnormal expression of RNA-binding proteins (RBPs) in various malignant tumors is closely related to the occurrence and development of tumors. However, the role of RBPs in acute myeloid leukemia (AML) is unclear.Methods: We downloaded harmonized RNA-seq count data and clinical data for AML from UCSC Xena, including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohorts. R package edgeR was used for differential expression analysis of 337 whole-blood data and 173 AML data. The prognostic value of these RBPs was systematically investigated by using univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO)–Cox regression analysis, and multivariate Cox regression analysis. C-index and calibration diagram were used to judge the accuracy of the model, and decision curve analysis (DCA) was used to judge the net benefit. The biological pathways involved were revealed by gene set enrichment analysis (GSEA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the protein–protein interaction (PPI) network performed lateral verification on the selected gene set and LASSO results.Results: A prognostic model of 12-RBP signature was established. In addition, the net benefit and prediction accuracy of the prognostic model and the mixed model based on it were significantly higher than that of cytogenetics. It is verified in the TARGET cohort and shows good prediction effect. Both the selection of our gene set and the LASSO results have high credibility. Most of these pathways are involved in the development of the disease, and they also accumulate in leukemia and RNA-related pathways.Conclusion: The prognosis model of the 12-RBP signature found in this study is an optimized biomarker that can effectively stratify the risk of AML patients. Nomogram based on this prognostic model is a reliable method to predict the median survival time of patients. This study expands our current understanding of the role of RBPs in the occurrence of AML and may lay the foundation for future treatment of the disease.

Highlights

Acute myeloid leukemia (AML) is a cancer of myeloid blood cells, characterized by clonal dilatation of myeloid precursors at different stages of differentiation, resulting in dysgenesis of normal blood cells, and bone marrow failure (Board, 2019)
UCSC Toil RNA-seq Recompute1 processing more than 20,000 unaligned RNA samples from The Cancer Genome Atlas (TCGA),2 Therapeutically Applicable Research to Generate Effective Treatments (TARGET),3 and Genotype-Tissue Expression (GTEx)4 datasets resulted in a combined cohort free of computational batch effects between different repository
A total of 6,278 genes with significant differences in expression were identified between TCGA—AML and GTEx—blood samples, which were tested by quasi-likelihood F-tests and generalized linear models in edgeR

Summary

Introduction

Acute myeloid leukemia (AML) is a cancer of myeloid blood cells, characterized by clonal dilatation of myeloid precursors at different stages of differentiation, resulting in dysgenesis of normal blood cells, and bone marrow failure (Board, 2019). It is the most common subtype of leukemia, with genetic diversity, a worldwide incidence of 3/100,000 per year, poor prognosis, and high mortality (Zhou and Chng, 2014; Döhner et al, 2015). Cytogenetics is an important prognostic factor for AML and is the basis of current risk classifications for the disease (Döhner et al, 2010; Grimwade et al, 2010). The role of RBPs in acute myeloid leukemia (AML) is unclear

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Conclusion