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Nat Med. 2019 Jan;25(1):130-140. doi: 10.1038/s41591-018-0262-9. Epub 2018 Dec 3.

Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma.

Author information

1
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
2
Cell Signalling Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
5
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
6
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
7
Biomedical and Biological Sciences Program, Harvard Medical School, Boston, MA, USA.
8
Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA.
9
School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy.
10
Center of Emphasis in Cancer, Paul L. Foster School of Medicine, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, USA.
11
Department of Oncology, University of Torino, Torino, Italy.
12
Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
13
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
14
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.
15
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. claudia.voena@unito.it.
16
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. roberto.chiarle@childrens.harvard.edu.
17
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. roberto.chiarle@childrens.harvard.edu.

Abstract

In 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-β. 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.

PMID:
30510251
PMCID:
PMC6556382
DOI:
10.1038/s41591-018-0262-9
[Indexed for MEDLINE]
Free PMC Article

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