Recent progress in clonal hematopoiesis: expanding the concept.

Abstract

Clonal hematopoiesis (CH) has emerged as a common age-related phenomenon and a central concept linking somatic mutations in hematopoietic stem cells to both malignant and non-malignant diseases. While initially recognized in the context of hematologic neoplasms, CH is now known to contribute to increased all-cause mortality, particularly through heightened risk of cardiovascular and inflammatory diseases. Frequent mutations in genes such as DNMT3A, TET2, and ASXL1 alter epigenetic regulation and immune signaling, thereby promoting clonal expansion and systemic consequences. Longitudinal studies have illuminated the dynamics of clonal growth and revealed how germline variants influence somatic selection. VEXAS syndrome, driven by UBA1-mutated CH, exemplifies the broader clinical reach of clonal expansion beyond malignancy. CH occupies an intermediate biological state with far-reaching implications. In this Progress in Hematology series, contributors explore the natural history, genetic underpinnings, and inflammatory manifestations of CH, offering insights into its role as both a biomarker and a potential therapeutic target in aging populations.