Clonal hematopoiesis (CH) is characterized by the expansion of hematopoietic stem and progenitor cells harboring somatic mutations, which confers an increased risk of hematologic malignancies and cardiovascular disease. Among CH-associated mutations, mutations affecting splicing factors (SFs), including splicing factor 3b subunit 1 (SF3B1), serine/arginine-rich splicing factor 2 (SRSF2), U2 small nuclear RNA auxiliary factor 1 (U2AF1), and zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2 (ZRSR2), play a unique role in promoting clonal expansion and leukemogenesis. In this review, we summarize recent findings on the role of SF mutations in CH progression, their interplay with other mutations (e.g., DNA methyltransferase 3 alpha (DNMT3A), ten-eleven translocation methylcytosine dioxygenase 2 (TET2) and isocitrate dehydrogenase 2 (IDH2)), and their impact on hematopoietic homeostasis. Epidemiological studies have demonstrated that SF-mutant CH exhibits an accelerated clonal expansion compared to other CH clones. Furthermore, murine models suggest that SF mutations alone do not inherently confer a growth advantage for clonal expansion but rather enhance disease phenotypes when co-existing with epigenetic mutations, such as IDH2 and TET2. These findings suggest that SF mutations contribute to CH expansion and malignant transformation through a synergistic interplay with other mutations and external factors such as inflammation. Given the clinical significance of SF mutations, ongoing research is focused on developing targeted therapies that modulate aberrant RNA splicing and prevent CH-driven leukemogenesis. Understanding the mechanisms underlying mutant spliceosome-mediated CH expansion may provide novel insights into early detection, risk stratification, and therapeutic interventions in hematologic malignancies.
Izumi et al. (Wed,) studied this question.