Splicing Factor Mutations in Clonal Hematopoiesis and Progression to Myeloid Neoplasms

Splicing factor (SF) mutations are recurrent driver alterations in myeloid neoplasms and also represent a distinctive class of mutations in clonal hematopoiesis (CH), an age-associated expansion of hematopoietic clones carrying somatic driver mutations. SF-mutant CH is characterized by relatively late emergence and accelerated clonal expansion in older individuals. This review summarizes current knowledge of the genetic features and clonal dynamics of SF-mutant CH. We discuss disease-associated molecular consequences of SF mutations, including dysregulation of innate immune and inflammatory signaling, R-loop accumulation associated with replication stress, altered stress granule dynamics, impaired minor intron splicing, and cooperative genetic interactions. We further consider candidate mechanisms that may contribute to age-dependent selection of SF-mutant clones during CH, including attenuated interferon responsiveness and telomere-dependent changes in replicative fitness. Together, current evidence highlights the unique biology of SF-mutant CH and the unresolved mechanisms underlying its preferential expansion in older individuals. Clarifying these mechanisms may improve risk stratification, inform early-intervention strategies, and advance our understanding of age-associated clonal evolution and leukemogenesis.