Splicing the Difference: Harnessing the Complexity of the Transcriptome in Hematopoiesis

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.