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

Massachusetts General Hospital. Gastrointestinal Unit. Center for the Study of Inflammatory Bowel Diseases. Boston, MA, USA / Harvard Medical School. Department of Medicine. Boston, MA, USA / Karolinska Institute. Department of Medicine. Unit of Clinical Allergy research. Stockholm, Sweden.
Massachusetts General Hospital. Gastrointestinal Unit. Center for the Study of Inflammatory Bowel Diseases. Boston, MA, USA / Harvard Medical School. Department of Medicine. Boston, MA, USA.
Karolinska Institute. Department of Medicine. Unit of Clinical Allergy research. Stockholm, Sweden.
Massachusetts General Hospital. Gastrointestinal Unit. Center for the Study of Inflammatory Bowel Diseases. Boston, MA, USA / Harvard Medical School. Department of Medicine. Boston, MA, USA.
Massachusetts General Hospital. Gastrointestinal Unit. Center for the Study of Inflammatory Bowel Diseases. Boston, MA, USA / Harvard Medical School. Department of Medicine. Boston, MA, USA.
Massachusetts General Hospital. Gastrointestinal Unit. Center for the Study of Inflammatory Bowel Diseases. Boston, MA, USA / Harvard Medical School. Department of Medicine. Boston, MA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.
Massachusetts General Hospital. Center for Computational and Integrative Biology. Boston, MA, USA / Harvard Medical School. Department of Genetics. Boston, MA, USA.
University of Texas Southwestern Medical Center. University of Texas Southwestern Medical Center. Dallas, TX, USA.
University Hospital Leuven and University of Leuven. Center for Human Genetics. Leuven, Belgium / University Hospital Leuven and University of Leuven.. Department of Hematology. Leuven, Belgium.
University College London. UCL Institute of Child Health. Molecular Immunology Unit. London, England, UK.
Hannover Medical School. Department of Pediatric Hematology and Oncology. Hannover, Germany.
Harvard Medical School. Departments of Genetics. Boston, MA, USA /
Harvard Medical School. Howard Hughes Medical Institute.Boston, MA, USA.
Massachusetts General Hospital. Gastrointestinal Unit. Center for the Study of Inflammatory Bowel Diseases. Boston, MA, USA / Harvard Medical School. Department of Medicine. Boston, MA, USA.

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.

Keywords in Portuguese

Mutações ativadoras de WASP
células linfocitárias
estabilidade genômica
células B e T
X-linked neutropenia

Keywords

WASP-activating mutations
B and T cells
lymphocyte cell survival
genomic stability
neutropenia

Publisher

Rockefeller University Press

Citation

WESTERBERG, Lisa S. et al. Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes. J. Exp. Med., v.207, n. 6, p.1145-1152, 2009.

DOI

10.1084/jem.20091245

ISSN

0022-1007

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/26608

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Open access

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