The genetics of human hematopoiesis and its disruption in disease.

Erik L Bao,Vijay G Sankaran,Aaron N Cheng

doi:10.15252/emmm.201910316

Abstract

Hematopoiesis, or the process of blood cell production, is a paradigm of multi‐lineage cellular differentiation that has been extensively studied, yet in many aspects remains incompletely understood. Nearly all clinically measured hematopoietic traits exhibit extensive variation and are highly heritable, underscoring the importance of genetic variation in these processes. This review explores how human genetics have illuminated our understanding of hematopoiesis in health and disease. The study of rare mutations in blood and immune disorders has elucidated novel roles for regulators of hematopoiesis and uncovered numerous important molecular pathways, as seen through examples such as Diamond‐Blackfan anemia and the GATA2 deficiency syndromes. Additionally, population studies of common genetic variation have revealed mechanisms by which human hematopoiesis can be modulated. We discuss advances in functionally characterizing common variants associated with blood cell traits and discuss therapeutic insights, such as the discovery of BCL11A as a modulator of fetal hemoglobin expression. Finally, as genetic techniques continue to evolve, we discuss the prospects, challenges, and unanswered questions that lie ahead in this burgeoning field.

Highlights

Every second, each one of us produces millions of diverse circulating blood cells—including erythrocytes, platelets, and leukocytes— through the coordinated process of hematopoiesis (Fig 1A–C)
We review more recent studies of common genetic variation impacting hematopoiesis which have further refined our understanding of this process
As a result of the rapid progress in this field, a critical follow-up question has arisen: How can we obtain meaningful biological insight from so many robust genetic signals? In the postGWAS era, the challenge has shifted to identify genetic regions associated with blood cell traits, and pinpoint the exact variants driving each signal, the genes targeted by these variants, and the cell types in which they act, in order to better understand mechanisms underlying the regulation of hematopoiesis in health and disease (Gallagher & Chen-Plotkin, 2018)

Summary

Introduction

Each one of us produces millions of diverse circulating blood cells—including erythrocytes, platelets, and leukocytes— through the coordinated process of hematopoiesis (Fig 1A–C). While rare variant genetics have done much to further characterize factors with known roles in blood cell production, such studies have connected previously unappreciated molecular pathways with hematopoiesis.

Results

Conclusion