Splicing Factor Mutations in Myeloid Malignancies

The discovery of recurrent somatic mutations affecting the RNA splicing machinery in 2011 revealed an unexpected class of driver mutations in hematologic malignancies. Remarkably, splicing factor (SF) mutations have emerged as some of the most frequent genetic lesions in myelodysplastic syndromes (MDS) and other dysplastic myeloid neoplasms, establishing aberrant RNA splicing as a major pathogenetic pathway in myeloid neoplasia. Subsequent studies have delineated their mutation-specific effects on RNA splicing and established their strong genotype-phenotype associations; consequently, SF mutations are now incorporated into contemporary disease classification and prognostic models. However, the mechanisms underlying their positive clonal selection and striking genotype-phenotype associations remain poorly understood, with co-mutations, clonal architecture, aging, and the hematopoietic microenvironment acting as important modifiers of disease expression. Elucidating how SF mutations interact with these modifiers to shape clonal fitness and disease phenotype remains a key challenge, while translating these biological insights into effective therapies represents the ultimate clinical goal.