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Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^± murine model.

ABSTRACT: The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton in hematopoietic cells and mutated in two severe immunodeficiency diseases with high incidence of cancer. Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in WASp and most frequently associated with lymphoreticular tumors of poor prognosis. X-linked neuropenia (XLN) is caused by gain-of-function mutations in WASp and associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To understand the role of WASp in tumorigenesis, we bred WASp⁺, WASp^-, and WASp-XLN mice onto tumor susceptible p53^+/- background and sub-lethally irradiated them to enhance tumor development. We followed the cohorts for 24 weeks and tumors were characterized by histology and flow cytometry to define the tumor incidence, onset, and cell origin. We found that p53^+/-WASp⁺ mice developed malignancies, including solid tumors and T cell lymphomas with 71.4% of survival 24 weeks after irradiation. p53^+/-WASp^- mice showed lower survival rate and developed various early onset malignancies. Surprisingly, the p53^+/-WASp-XLN mice developed malignancy mostly with late onset, which caused delayed mortality in this colony. This study provides evidence for that loss-of-function and gain-of-function mutations in WASp influence tumor incidence and onset.

SUBMITTER: Keszei M

PROVIDER: S-EPMC6209425 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53<sup>±</sup> murine model.

Keszei Marton M Kritikou Joanna S JS Sandfort Deborah D He Minghui M Oliveira Mariana M S MMS Wurzer Hannah H Kuiper Raoul V RV Westerberg Lisa S LS

Oncoimmunology 20180730 9

The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton in hematopoietic cells and mutated in two severe immunodeficiency diseases with high incidence of cancer. Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in WASp and most frequently associated with lymphoreticular tumors of poor prognosis. X-linked neuropenia (XLN) is caused by gain-of-function mutations in WASp and associated with acute myeloid leukemia (AML) and myelodysplastic syndr ...[more]

PMID: 30393584

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Project description:Wiskott-Aldrich syndrome (WAS) is characterized by X-linked thrombocytopenia, eczema, immunodeficiency, recurrent infections and increased risk of autoimmunity and malignancies. WAS is caused by mutations in the WAS gene, which encodes the exclusively hematopoietic WAS protein (WASp) that is classically characterized as aν actin nucleator. However, disruption of F-actin polymerization by WAS mutations can not account for many aspects of WAS pathogenesis. Ignorance of other functions of WASP precludes in-depth understanding of the pathogenic effects of mutant WASP, and therefore hampers development of effective therapy. Here we generated induced pluripotent stem cells (iPSCs) from WAS patients (WAS-iPSC) bearing different mutations and corresponding isogenic iPSCs in which the pathogenic mutations had been corrected by targeted genome editing. Hematopoietic cells differentiated from WAS-iPSCs not only recapitulated known disease phenotypes, but also revealed novel defects of WASP deficient cells. WASP co-localized with nuclear pores, nucleoli, nuclear speckles and PML bodies by immunocytochemistry and/or serial block face scanning microscopy (SBF-SEM). MudPIT (multi-dimensional protein identification technology) analysis revealed that WASP physically interacted with nuclear body components, nuclear structural proteins, chromatin modifying complexes, and many RNA-binding proteins including major components of the spliceosome. Next-generation sequencing captured a dramatic global change of alternative splicing in WAS patient cells. WAS mutation impacted splicing of multiple genes frequently mutated in myelodysplastic syndrome and other cancers. RNA sequencing showed that WAS-iPSC derived immune cells misregulated many cell cycle regulators, tumor suppressors, immune function genes and splicing factors, and activated gene networks that drive cancer development and inflammatory diseases. Together these data uncovered previously unappreciated functions of the WASP and provided a mechanistic understanding of the pathogenesis of malignancy and autoimmunity in the most severe form of WAS. These new knowledge could help develop targeted therapy for WAS in the future.

Dataset Information

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^± murine model.

Publications

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53<sup>±</sup> murine model.

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Dataset Information

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53± murine model.

Publications

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53<sup>±</sup> murine model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53^± murine model.