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.

Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding

“…75 In addition, these patients show an increased predisposition for AML or MDS. 76 In classical Wiskott-Aldrich syndrome patients, the prevalence of malignancy is 13-22%, mostly due to development of lymphoma, but also to lymphoblastic leukemia, MDS or MPD. 76 The thrombocytopenia is likely caused by increased platelet removal.…”

“…In classical Wiskott-Aldrich syndrome patients, the prevalence of malignancy is 13-22%, mostly due to development of lymphoma, but also to lymphoblastic leukemia, MDS or MPD. 76 The thrombocytopenia is likely caused by increased platelet removal. In Was -deficient mice, platelet turnover was shortened, with proteomic evidence for alterations in proteins of metabolic and proteasomal pathways.…”

Wiskott-Aldrich syndrome protein senses irradiation-induced DNA damage to coordinate the cell-protective Golgi dispersal response in human T and B lymphocytes

“…[43][44][45] In the irradiation-induced murine model of cancer, compared with p53 1/2 WASp 1/1 mice, p53 1/2 WASp 2/2 mice have lymphoma. 46 Accordingly, GOLPH3 functions as an oncoprotein, whereas WASp functions as a tumor-suppressor protein, at least in a subset of cancers. Thus the effect of GOLPH3 or WASp dysfunction on DNA damage-induced GDR is likely modulated by the cell lineage, cancer subtype, or both.…”

Higher Incidence of B Cell Malignancies in Primary Immunodeficiencies: A Combination of Intrinsic Genomic Instability and Exocytosis Defects at the Immunological Synapse

“…Impaired NK cells lytic functions are also observed in WAS patients and WASp deficient mice (85,86,106,107). In the absence of WASp, the NK cell IS is immature and lacks multiple signaling molecules.…”

“…The tumor incidence in WAS is estimated to be 13%–22% with a median age of onset of 9.5 years and with poor prognosis ( 98 , 99 ) and most frequently lymphoreticular tumors including non-Hodgkin lymphoma (76% of the total tumors associated with WAS), Hodgkin lymphoma, and Burkitt lymphoma ( 99 – 105 ). Both reduced tumor immunosurveillance by cytotoxic cells ( 85 – 87 , 106 , 107 ) and intrinsic cell transformation ( 107 – 109 ) contribute to malignancies in WAS. In the first XLN family with constitutively active WASp (WAS-L270P) ( 82 ), two out of six affected males have developed myelodysplastic syndrome and leukemia and one unrelated XLN patient with the WAS-I294T mutation developed myelodysplastic syndrome ( 83 ).…”