Clonal hematopoiesis

Abstract

Cancer results from multistep pathogenesis, yet the pre-malignant states that precede the development of many hematologic malignancies have been difficult to identify. Recent genomic studies of blood DNA from tens of thousands of people have revealed the presence of remarkably common, age-associated somatic mutations in genes associated with hematologic malignancies. These somatic mutations drive the expansion from a single founding cell to a detectable hematopoietic clone. Owing to the admixed nature of blood that provides a sampling of blood cell production throughout the body, clonal hematopoiesis is a rare view into the biology of pre-malignancy and the direct effects of pre-cancerous lesions on organ dysfunction. Indeed, clonal hematopoiesis is associated not only with increased risk of hematologic malignancy, but also with cardiovascular disease and overall mortality. Here we review rapid advances in the genetic understanding of clonal hematopoiesis and nascent evidence implicating clonal hematopoiesis in malignant and non-malignant age-related disease.

Keywords: Aging; Hematopoietic stem cell; Pre-leukemia.

Figure 1:

(A) Prevalence of clonal hematopoiesis per decade in three recent studies. (B) Recurrent mutations identified from exome sequence data from three recent studies.

Figure 2:

Mechanisms of clonal advantage in HSCs. Red box represents injury and cell death. Enhanced self-renewal and impaired differentiation may have similar HSC dynamics but differences in gene expression that primarily enforce self-renewal or impair differentiation, respectively.