CHIP ahoy: charting a decade of discovery in clonal hematopoiesis

Abstract

Clonal hematopoiesis (CH) involves the expansion of hematopoietic stem cells with ageacquired mutations linked to myeloid malignancy. Advances in next-generation and single-cell sequencing, along with computational modeling, have expanded our ability to detect both common and rare CH drivers, including single-nucleotide variants and mosaic chromosomal alterations, with increasing sensitivity. While sequencing methods differ in accuracy, cost, and ability to detect low-frequency variants, they have deepened our understanding of CH biology. A growing body of evidence has identified both somatic drivers, such as variants in DNMT3A, TET2, and ASXL1, and germline genetic variants that modify CH risk, highlighting the complex interplay between inherited and acquired factors. These collective discoveries are guiding the development of targeted therapies and interventions, particularly for individuals at risk of progression to myeloid neoplasms or cardiovascular disease. Additionally, CH is emerging as a clinically relevant factor in the treatment of solid tumors, where it may influence the tumour microenvironment, treatment response and the risk of therapy-related complications. Risk stratification models are facilitating earlier identification and monitoring of high-risk individuals, enabling personalized treatment decisions. The scope of CH management continues to expand, from surveillance to intervention, with ongoing trials testing preventive strategies in high-risk populations. Emerging trial frameworks emphasize risk stratification, age-appropriateness, inclusive recruitment, decentralized trial models, and the use of traditional clinical and novel endpoints. Together, these advances reflect a shift from passive observation to proactive intervention, charting a course for early detection, precision treatment, and prevention in CH care.