RNA splicing alterations induce a cellular stress response associated with poor prognosis in AML

Abstract

Anande et al RNA splicing alterations in AML 3 Key Points • Widespread and recurrent alternative splicing differences exist between AML patients with good or poor prognosis • Missplicing of RNA splicing factors leads to altered splicing of their target transcripts • Aberrant splicing of protein translation genes triggers the induction of an integrated stress response and concomitant inflammatory response • Alternative RNA splicing information can be used to improve the accuracy of existing prognostic algorithms in AML Anande et al RNA splicing alterations in AML 4Abstract RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are relatively uncommon in Acute Myeloid Leukemia (AML, < 20%). We examined whether RNA splicing differences exist in AML even in the absence of splicing factor mutations. Analyzing RNA-seq data from two independent cohorts of AML patients, we identified recurrent differential alternative splicing between patients with poor and good prognosis. These alternative splicing events occurred even in patients without any discernible splicing factor mutations. The alternative splicing events recurrently occurred in genes involved in specific molecular functions, primarily related to protein translation. Developing informatics tools to predict the functional impact of alternative splicing on the translated protein, we discovered that ~45% of the splicing events directly affected highly conserved protein domains.Several splicing factors were themselves misspliced in patients, and the splicing of their target transcripts were also altered. By studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELN Adv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Lastly, using machine learning techniques, we identified a set of four genes whose alternative splicing can refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance. Anande et alRNA splicing alterations in AML 5

A Bayesian model for unsupervised detection of RNA splicing based subtypes in cancers

“…Notably, two RBPs with the most significantly enriched DS junction overlap include SRSF1 (2.48%) and U2AF2 (1.54%), both of which have known roles in promoting expression of antiapoptotic isoforms of oncogenes in several hematopoietic maglicanies 30 . Another candidate splicing regulator which appeared to be differentially expressed and spliced between the signal and background groups is HNRNPC (2.44%), which has been implicated in AML in a recent study 31 . Next, we analyzed eCLIP data for each RBP to test whether there was evidence for direct RBP binding around the tile's differentially spliced junctions.…”