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.