Tracking hematopoietic stem cells and their progeny using whole-genome sequencing

Henry Lee-Six,David G Kent

doi:10.1016/j.exphem.2020.01.004

Abstract

Despite decades of progress in our understanding of hematopoiesis through the study of animal models and transplantation in humans, investigating physiological human hematopoiesis directly has remained challenging. Questions on the clonal structure of the human hematopoietic stem cell (HSC) pool, such as "how many HSCs are there?" and "do all HSC clones actively produce all blood cell types in equal proportions?" remain open. These questions have inherent value for understanding normal human physiology, but also directly inform our comprehension of the process by which the system is subverted to drive diseases of the blood, in particular blood cancers and bone marrow failure syndromes. The critical link between normal and abnormal hematopoiesis is perhaps best illustrated by the recent discovery of clonal hematopoiesis in healthy people with no abnormal blood parameters. In such individuals, large clones derived from single cells are present and are dominant relative to their normal counterparts, but their presence does not necessitate abnormal blood cell production. Intriguingly, however, these individuals are also at a significantly greater risk of developing leukemias and of cardiovascular events, underscoring the importance of understanding how blood stem cell clones compete against each other.

Highlights

To determine what is abnormal, we first need to understand the range of clone size distributions that should be considered “normal.” Does clonal hematopoiesis represent the detectable tail of a distribution of clone sizes across the whole population
As clonal hematopoiesis is covered in other articles in this collection [2,3,6], we focus this review on recent studies that have used whole-genome sequencing to track clonal dynamics in unperturbed human hematopoiesis and touch upon future applications of the approach in studying how aberrations in clonal dynamics are evidenced in disease
Whole-genome sequencing as a method to track unperturbed human hematopoiesis is a natural extension of decades of work in animal models using different markers to follow cells and opens opportunities for having a more direct assessment of what hematopoietic stem cell (HSC) do in vivo throughout aging

Summary

Introduction

To determine what is abnormal, we first need to understand the range of clone size distributions that should be considered “normal.” Does clonal hematopoiesis represent the detectable tail of a distribution of clone sizes across the whole population The presence of somatic mutations in genes that are found in myeloid malignancies (e.g., TET2, DNMT3A) suggests the latter, but a number of possible scenarios could explain their existence (Figure 1). As clonal hematopoiesis is covered in other articles in this collection [2,3,6], we focus this review on recent studies that have used whole-genome sequencing to track clonal dynamics in unperturbed human hematopoiesis and touch upon future applications of the approach in studying how aberrations in clonal dynamics are evidenced in disease

Methods

Findings

Conclusion