Clonality in haematopoietic stem cell ageing

Abstract

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.

Keywords: Ageing; Cell-Intrinsic; Clonal haematopoiesis of indeterminate potential; DNMT3A; Environment; TET2.

Fig. 1

Is CHIP dependent on the environment or driven by cell intrinsic factors? Upper panel: CHIP is driven cell-intrinsically. Here, the time to acquisition of the CHIP mutation (Mut.) and the change in fitness conferred by the mutation are the determining factors of clonal outgrowth. Average time to mutation depends on a variety of factors, including sequence context of the mutation, mutation rate and genotoxic events, such as chemotherapy. Lower Panel: CHIP is driven through cell-intrinsic and environmental factors. Here, the time to acquisition of the CHIP mutation (Mut.) and the change in fitness conferred by the mutation are again determining factors. However, clonal outgrowth is enhanced or enabled by environmental changes (Env. yellow background). Supposed environmental factors are discussed in the main text and include inflammation and other age-related changes.