Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects.

Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.

Clonality in haematopoietic stem cell ageing.

Clonal haematopoiesis of indeterminate potential (CHIP) is widespread in the elderly. CHIP is driven by somatic mutations in leukaemia driver genes, such as Janus Kinase 2 (JAK2), Tet methylcytosine dioxygenase 2 (TET2), ASXL Transcriptional Regulator 1 (ASXL1) and DNA (cytosine-5)-methyltransferase 3A (DNMT3A), leading to reduced diversity of the blood pool. CHIP carries an increased risk for leukaemia and cardiovascular disease. Apart from mutations driving CHIP, environmental factors such as chemokines and cytokines have been implicated in age-dependent multimorbidities associated with CHIP. However, the mechanism of CHIP onset and the relationship with environmental and cell-intrinsic factors remain poorly understood. Here we contrast cell-intrinsic and environmental factors involved in CHIP development and disease propagation.

Age-related clonal haemopoiesis is associated with increased epigenetic age.

Age-related clonal haemopoiesis (ARCH) in healthy individuals was initially observed through an increased skewing in X-chromosome inactivation [1]. More recently, several groups reported that ARCH is driven by somatic mutations [2], with the most prevalent ARCH mutations being in the DNMT3A and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers [2]. ARCH also confers an increased risk for non-haematological diseases, such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor [3,4]. Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly used tools to measure age acceleration are epigenetic clocks: they are based on age-related methylation differences at specific CpG sites [5]. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities [5,6]. Here we present evidence of accelerated epigenetic age in individuals with ARCH.