Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes

Abstract

X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP–expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP–expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP–expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability.

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“…WASP is exclusively expressed in hematopoietic cells and transduces signals from the cell surface to the actin cytoskeleton. The actin cytoskeleton is required to control cell-cell interaction, cell movement, cell signaling and cell division [98]. WASP is inactive in the cytoplasm due to an auto-inhibitory mechanism mediated by interaction between the verprolin-cofilin homology domains acidic region (VCA) and the GTPase-binding domain (GBD) [99].…”

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“…3-10 XLN is caused by mutations that destroy the auto-inhibitory folding of WASp thereby rendering WASp constitutively active. 11-15 XLN patients show bone marrow arrest at the promyelocyte stage associated with development of myelodysplastic syndrome and acute myeloid leukemia. This is associated with aberrant segregation of chromosomes to the daughter cells and impaired cytokinesis during mitosis, leading to increased cell death.…”

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“…These mutations were initially predicted to lead to constitutively active WASp and as a consequence cells would have increased load of polymerized actin [17]. Several laboratories have now confirmed this hypothesis and shown markedly increased polymerized actin in neutrophils, in macrophages, and in B and T cells [18–22] (Keszei and Westerberg-unpublished observation). XLN patients suffer from recurrent bacterial infections because of severe neutropenia and monocytopenia [17, 18, 20] and they may develop cytogenetic changes indicative of chromosomal instability, myelodysplasia, or acute myeloid leukemia [18–20, 22].…”