Wiskott-Aldrich Syndrome Protein Regulates Nuclear Organization, Alternative Splicing and Cell Proliferation

Abstract

Wiskott-Aldrich syndrome (WAS), caused by mutations in the WASP protein, displays immunological dysfunctions and predisposition to cancer. Despite studies in cell lines and mouse models the molecular mechanisms of WAS remain obscure. We generated induced pluripotent stem cells (iPSCs) from patients with WAS (WAS-iPSCs) and isogenic gene-corrected iPSCs by genome editing. Immune cells derived from WAS-iPSCs, genetically engineered B lymphoblastoid cell lines, and patient primary lymphocytes were subjected to imaging, proteomic and transcriptomic analyses. The WAS-iPSC model not only recapitulated known disease phenotypes but also revealed, for the first time, roles of WASP in the organization of the nucleolus and nuclear speckles and PML nuclear bodies. WASP interacts with components of the nucleolus and nuclear speckles, including chromatin modifiers and splicing factors. Innate and adaptive immune cells from WAS patients display global dysregulation of cell cycle regulation and alternative splicing. WASP mutation is sufficient to drive an accelerated cell cycle and tumor-promoting splicing changes. Our data show that WASP acts as a tumor suppressor and specific WASP mutants behave as oncogenes and cause cellintrinsic alterations that predispose patients to cancer.