Work

Unveiling splicing disruptions due to common somatic variants in acute myeloid leukemia

Year: 2025

Type: article

Abstract: Acute Myeloid Leukemia (AML) is a genetically and clonally heterogeneous blood malignancy characterized by somatic gene mutations influencing disease biology. Despite advances in genomic analyses, splicing alterations associated with AML mutations remain underexplored. In this study, we systematically analyzed 914 single nucleotide variants previously found in 1540 AML patients and integrated DNA and RNA sequencing data from an additional 639 cases obtained from the BeatAML and TCGA-LAML cohorts. We identified 125 somatic variants in 32 genes with predicted splicing impact, including traditionally categorized missense/nonsense mutations. Among the 36 variants tested experimentally, 17 were validated through RNA-seq and/or minigene assays, with the latter providing support when RNA-seq evidence was limited. Validated splicing-associated variants (SAVs) frequently induced exon skipping or cryptic splice site activation in AML-associated genes such as EZH2, FLT3, ASXL1, IDH1, and U2AF1. In several cases, these splicing changes altered conserved protein domains or were predicted to trigger nonsense-mediated decay. Our findings reveal a previously underappreciated contribution of cis-acting SAVs to AML pathogenesis, highlighting the need for integrative prediction–validation strategies to uncover their functional and potential therapeutic relevance.

Source: Human Genomics

DOI: 10.1186/s40246-025-00842-6