EVALUATING CLONAL HEMATOPOIESIS IN THE ELDERLY AND RISK OF HEMATOLOGIC MALIGNANCY

Abstract

Clonal hematopoiesis (CH) is an increasingly recognized age-associated phenomenon in which a substantial proportion of hematopoietic cells derive from a single mutated stem cell. This study investigates the prevalence, genetic landscape, and malignancy risk associated with CH in the elderly, while also exploring the interconnection between CH and cellular senescence. A comprehensive secondary analysis of recent genomic and clinical studies was conducted, focusing on elderly cohorts. Our findings reveal a strong age-dependent rise in CH prevalence, reaching 38.6% in individuals aged 80 and above. The most frequently mutated genes included DNMT3A (38.5%), TET2 (29.2%), and ASXL1 (17.8%), with mutation burden positively correlating with malignancy risk. Notably, a variant allele frequency (VAF) above 20% was associated with a 25.6% probability of developing hematologic malignancies, underscoring clone size as a critical prognostic indicator. Concurrently, aged hematopoietic stem cells exhibited significantly elevated levels of senescence markers such as p16, IL-6, and MMP-3, implicating the senescence-associated secretory phenotype (SASP) in disrupting the bone marrow microenvironment. Figures and simulations reinforced the biological plausibility of these findings, illustrating pronounced shifts in inflammatory and stress-related markers in aged tissues. The study suggests that CH and senescence operate synergistically to compromise hematopoietic homeostasis and elevate oncogenic risk. These insights advocate for routine genomic and inflammatory profiling in elderly individuals to enable early detection and risk stratification. Furthermore, targeting senescent cells with emerging senolytic therapies may offer a novel preventative strategy against age-related hematologic malignancies. Collectively, the results highlight the importance of integrating CH monitoring and senescence modulation into the future framework of geriatric hematologic care.