Introduction to a review series on mechanisms and clinical implications of clonal hematopoiesis

The adult blood system is organized in a hierarchical fashion, whereby short-lived mature cells are continuously replenished via a differentiation cascade that originates from a pool of long-lived stem and progenitor cells. The functional unit composed of a single stem cell and all of its progeny is commonly referred to as a clone. Given that a healthy human blood system consists of many thousands of these clones, hematopoiesis can be thought of as a complex ecosystem in which the size of individual clones may fluctuate over time. By studying the pattern of X-chromosome inactivation in females, it was shown about 25 years ago that individual clones may expand in healthy individuals with no overt hematological disease.¹  The last decade has seen a tremendous acceleration in our understanding of the mechanisms that may underlie expansion of a single clone, and the field is now poised to explore how these new insights may turn out to be clinically actionable.

In this series, recent advances in our understanding of the basic science, as well as the clinical relevance, of clonal hematopoiesis are highlighted. The series includes the following review articles:

• “Clonal hematopoiesis: mechanisms driving dominance of stem cell clones” by Grant A. Challen and Margaret A. Goodell

• “Clonal hematopoiesis and risk for hematologic malignancy” by Julia T. Warren and Daniel C. Link

• “Clonal hematopoiesis and nonhematologic disorders” by Siddhartha Jaiswal

• “Clonal hematopoiesis in the inherited bone marrow failure syndromes” by Frederick D. Tsai and R. Coleman Lindsley

• “What to tell your patient with clonal hematopoiesis and why: insights from 2 specialized clinics” by David P. Steensma and Kelly L. Bolton

The etiology of malignant hematopoietic diseases is commonly viewed as a stepwise process of mutation acquisition coupled with clonal evolution, giving rise to increasingly malignant cells. Unsurprisingly, therefore, the identification of mutations that cause clonal hematopoiesis has direct relevance to research efforts aiming to decipher the molecular processes that underlie the earliest steps of leukemogenesis. What came as more of a surprise, however, is the substantial impact of clonal hematopoiesis in terms of increasing the risk of developing nonhematological diseases, such as cardiovascular disease. Therefore, the phenomenon of clonal hematopoiesis touches on a diverse range of biomedical research fields.

It is hoped that the selection of reviews in this issue does justice to the broad relevance of clonal hematopoiesis and also may entice researchers from a given field to broaden their horizons by exploring the importance of this very topical phenomenon more widely.