The mouse homolog of the mutant WASp responsible for human X-linked neutropenia renders granulopoiesis ineffective

Masahiro Ikeda; Muneyoshi Futami; Bidisha Chanda; Masayuki Kobayashi; Kiyoko Izawa; Arinobu Tojo

doi:10.1016/j.bbrc.2022.07.037

The mouse homolog of the mutant WASp responsible for human X-linked neutropenia renders granulopoiesis ineffective

Biochem Biophys Res Commun. 2022 Sep 24:622:177-183. doi: 10.1016/j.bbrc.2022.07.037. Epub 2022 Jul 14.

Authors

Masahiro Ikeda¹, Muneyoshi Futami², Bidisha Chanda³, Masayuki Kobayashi⁴, Kiyoko Izawa⁵, Arinobu Tojo⁶

Affiliations

¹ Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan; Division of Palliative Therapy, Palliative Care Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Japan.
² Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan; Project Division of Innovative Diagnostics Technology Platform, The Institute of Medical Science, The University of Tokyo, Japan. Electronic address: m-futami@ims.u-tokyo.ac.jp.
³ Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan.
⁴ Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan; Department of Hematology, Tokyo Metropolitan Bokutoh Hospital, Japan.
⁵ Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Japan.
⁶ Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan; Institute of Innovation Advancement, Tokyo Medical and Dental University, Japan.

PMID: 35932529
DOI: 10.1016/j.bbrc.2022.07.037

Abstract

Severe congenital neutropenia (SCN) is characterized by severe neutropenia and recurrent critical infections. X-linked neutropenia (XLN) is caused by a gain-of-function mutation in the Wiskott-Aldrich syndrome gene (WAS), the product of which (WASp) is expressed only in blood cells, especially during neutrophil maturation. To investigate the mechanism of neutropenia, we established a novel knock-in mouse line expressing WASp-I292T. WASp-I292T neutrophils exhibited activated (dysregulated) actin polymerization. Although WASp-I292T mice did not recapitulate neutropenia, neutrophil levels were increased in the bone marrow, and extramedullary hematopoiesis was observed. Bone marrow neutrophils from WASp-I292T mice exhibited attenuated transmigration. These abnormalities were associated with downregulation of NFκB and TP53 and faulty activation of their downstream pathways.

Keywords: Severe congenital neutropenia; WASp; Wiskott-Aldrich syndrome; X-linked neutropenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Animals
Congenital Bone Marrow Failure Syndromes / genetics
Hematopoiesis / genetics
Humans
Mice
Neutropenia* / genetics
Neutrophils / metabolism
Wasps*
Wiskott-Aldrich Syndrome Protein / genetics
Wiskott-Aldrich Syndrome Protein / metabolism

Substances

Actins
Wiskott-Aldrich Syndrome Protein