Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma.
AffiliationDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
MetadataShow full item record
AbstractIn T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-?. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.
CitationMenotti M, Ambrogio C, Cheong TC, Pighi C, Mota I, Cassel SH, et al. Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma. Nat Med. 2018 Dec 3.
- Cutting edge: WIP, a binding partner for Wiskott-Aldrich syndrome protein, cooperates with Vav in the regulation of T cell activation.
- Authors: Savoy DN, Billadeau DD, Leibson PJ
- Issue date: 2000 Mar 15
- NPM-ALK phosphorylates WASp Y102 and contributes to oncogenesis of anaplastic large cell lymphoma.
- Authors: Murga-Zamalloa CA, Mendoza-Reinoso V, Sahasrabuddhe AA, Rolland D, Hwang SR, McDonnell SR, Sciallis AP, Wilcox RA, Bashur V, Elenitoba-Johnson K, Lim MS
- Issue date: 2017 Apr
- T-cell receptor ligation causes Wiskott-Aldrich syndrome protein degradation and F-actin assembly downregulation.
- Authors: Watanabe Y, Sasahara Y, Ramesh N, Massaad MJ, Yeng Looi C, Kumaki S, Kure S, Geha RS, Tsuchiya S
- Issue date: 2013 Sep
- Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation.
- Authors: Sasahara Y, Rachid R, Byrne MJ, de la Fuente MA, Abraham RT, Ramesh N, Geha RS
- Issue date: 2002 Dec
- WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1alpha.
- Authors: Gallego MD, de la Fuente MA, Anton IM, Snapper S, Fuhlbrigge R, Geha RS
- Issue date: 2006 Feb