Genome editing and induced pluripotent stem cells model reveal novel roles of WASP in cancer

Abstract

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease that caused by the genetic defect in WAS protein (WASP). The classical syndrome is characterized by thrombocytopenia, immunodeficiency, atopy, autoimmunity, and malignancy, leading to premature death in severe patients. Studies have shown that 13% to 22% of patients develop cancer with the only average onset of 9.5 years; however, the molecular mechanism underlying the early onset and high morbidity of cancer in WAS is still an unsolved issue. As the founding member of actin nucleation-promoting factors, WASP plays a critical role in mediating actin polymerization and remodeling the cytoskeleton. Nevertheless, this function fails to explain malignancy development. Here, by using induced pluripotent stem cells (iPSCs) generated from WAS patient, we found that WAS mutant cells have an abnormal cell cycle. The cell cycle-related genes/pathways are significantly deregulated. We show that WAS deficiency leads to of splicing regulation and epigenetic regulation involved in cell cycle. We confirmed our findings in 4 independent patients with different mutations using macrophages, T, B, and dendritic cells. Interestingly, WASP’s multifaceted function in the nucleus results in synergistic disruption of cell cycle regulation when it is mutated. Taken together, our finding identified a new function of WASP in the cell cycle, which offers a potential target for predicting early cancer in WAS patient as well as a new therapy.