Deciphering the role of SF3B1 in hematopoiesis

Abstract

Hematologic malignancies claim the lives of many people every year, yet we lack a complete understanding of the mechanisms of pathogenesis behind them. Myelodysplastic Syndromes (MDS) are a group of hematologic malignancies characterized by bone marrow failure; MDS greatly decreases the life quality and expectancy of patients, and carries the risk of progression to leukemia. RNA sequencing analysis of MDS patient samples has showed that mutations in splicing factors are highly recurrent and frequently act as driver mutations. In addition to being altered in MDS, there is ample evidence that splicing factors play important roles in the process of hematopoiesis. The most commonly mutated factor in MDS is Splicing Factor 3B, subunit 1 (SF3B1) yet its particular function in hematopoiesis is poorly understood. The aims of this study were to explore the role of Sf3b1 in hematopoiesis and to investigate the cellular mechanisms altered when Sf3b1 protein function is disrupted. For this purpose we used a zebrafish sf3b1 loss-of-function mutant. We evaluated the status of primitive and definitive hematopoiesis. We found that formation of hematopoietic stem cells is impaired and maturation of primitive myeloid and erythroid cells is blocked. RNA sequencing of primitive erythroid cells of mutant and wild-type siblings showed that there are gene expression and splicing misregulation in mutant erythroid cells. Finally, flow cytometry studies led us to the discovery that mutant erythroid cells undergo a cell cycle arrest largely mediated by TGFbeta, which prevents their expansion. The results of this study indicate that sf3b1 null zebrafish are a useful model to analyze the molecular mechanisms of hematopoietic dysfunction caused by defects in SF3B1 and help us advance towards improved therapeutics for hematopoietic malignancies.