Abstract
Immunodeficiency is associated with cancer risk. Accordingly, hematolymphoid cancers develop in Wiskott–Aldrich syndrome (WAS), an X-linked primary immunodeficiency disorder (PID) resulting from the deficiency of WAS-protein (WASp) expressed predominantly in the hematolymphoid cell lineages. Despite the correlation between WASp deficiency and hematolymphoid cancers, the molecular mechanism underlying the oncogenic role of WASp is incompletely understood. Employing the WASp-sufficient and WASp-deficient cell-pair model of human T and B lymphocytes, we show that WASp deficiency differentially influences hyperactivation versus inhibition of both CDC42:ERK1/2 and NF-κB:AP-1 pro-oncogenic signaling pathways in nonmalignant versus malignant T and B lymphocytes. Furthermore, WASp deficiency induces a cell-type specific up/down-modulation of the DNA-binding activities of NF-κB, AP-1, and multiple other transcription factors with known roles in oncogenesis. We propose that WASp functions as a putative “tumor-suppressor” protein in normal T and B cells, and “oncoprotein” in a subset of established T and B cell malignancies that are not associated with the NPM-ALK fusion.
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Acknowledgements
This work was supported in part by the NIH, National Institute of Allergy and Infectious Diseases (NIAID) grants R21AI138051 and R01AI146380 (to YMV), the University of Iowa Dance Marathon (UIDM) research award (to SSH), Research Bridge Award from the Carver College of Medicine (to YMV), and the Endowment from the Mary Joy and Jerre Stead Foundation (to YMV). A subset of data was obtained at the Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa. We thank the UIDM for supporting the research laboratory space where this work was carried out.
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This work was supported in part by the NIH grant R21AI138051 and R01AI146380 (to YMV).
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SSH generated all CRISPR/Cas9-mediated WAS gene KO cellular models and performed the majority of molecular and cellular assays. KKW performed all Western blots, flow studies, and cell-survival assays. YMV conceived the study, designed the experiments, analyzed and interpreted the data, and wrote the paper.
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Han, SS., Wen, KK. & Vyas, Y.M. Deficiency of Wiskott–Aldrich syndrome protein has opposing effect on the pro-oncogenic pathway activation in nonmalignant versus malignant lymphocytes. Oncogene 40, 345–354 (2021). https://doi.org/10.1038/s41388-020-01533-3
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DOI: https://doi.org/10.1038/s41388-020-01533-3