Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
EMBO Mol Med. 2019 Aug;11(8):e10316. doi: 10.15252/emmm.201910316. Epub 2019 Jul 17.
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.
造血，即血细胞的生成过程，是多谱系细胞分化的典范，已得到广泛研究，但在许多方面仍未被完全理解。几乎所有临床上可测量的造血特征都表现出广泛的变异性和高度的遗传性，这突显了遗传变异在这些过程中的重要性。本综述探讨了人类遗传学如何阐明我们对健康和疾病中造血的理解。血液和免疫疾病中罕见突变的研究揭示了造血调控因子的新作用，并通过 Diamond-Blackfan 贫血和 GATA2 缺陷综合征等例子揭示了许多重要的分子途径。此外，对常见遗传变异的群体研究揭示了人类造血可以被调节的机制。我们讨论了在功能上描述与血细胞特征相关的常见变异的进展，并讨论了治疗方面的见解，例如发现 BCL11A 是胎儿血红蛋白表达的调节剂。最后，随着遗传技术的不断发展，我们讨论了这一迅速发展的领域面临的前景、挑战和未解决的问题。
