Maul-Newby Hannah M, Halene Stephanie
Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
Exp Hematol. 2024 Dec;140:104655. doi: 10.1016/j.exphem.2024.104655. Epub 2024 Oct 10.
Alternative splicing has long been recognized as a powerful tool to expand the diversity of the transcriptome and the proteome. The study of hematopoiesis, from hematopoietic stem cell maintenance and differentiation into committed progenitors to maturation into functional blood cells, has led the field of stem cell research and cellular differentiation for decades. The importance of aberrant splicing due to mutations in cis has been exemplified in thalassemias, resulting from aberrant expression of β-globin. The simultaneous development of increasingly sophisticated technologies, in particular the combination of multicolor flow cytometric cell sorting with bulk and single-cell sequencing, has provided sophisticated insights into the complex regulation of the blood system. The recognition that mutations in key splicing factors drive myeloid malignancies, in particular myelodysplastic syndromes, has galvanized research into alternative splicing in hematopoiesis and its diseases. In this review, we will update the audience on the exciting novel technologies, highlight alternative splicing events and their regulators with essential functions in hematopoiesis, and provide a high-level overview how splicing factor mutations contribute to hematologic malignancies.
可变剪接长期以来一直被认为是扩展转录组和蛋白质组多样性的有力工具。造血研究，从造血干细胞的维持、分化为定向祖细胞到成熟为功能性血细胞，几十年来一直引领着干细胞研究和细胞分化领域。由于顺式突变导致的异常剪接的重要性在β地中海贫血中得到了体现，β地中海贫血是由β珠蛋白的异常表达引起的。越来越复杂的技术的同时发展，特别是多色流式细胞术细胞分选与大量测序和单细胞测序的结合，为血液系统的复杂调控提供了深入的见解。关键剪接因子的突变驱动髓系恶性肿瘤，特别是骨髓增生异常综合征，这一认识激发了对造血过程及其疾病中可变剪接的研究。在这篇综述中，我们将向读者介绍令人兴奋的新技术，重点介绍在造血过程中具有重要功能的可变剪接事件及其调节因子，并概述剪接因子突变如何导致血液系统恶性肿瘤。
