Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma.
Menotti, Matteo Ambrogio, C Cheong, TC Pighi, C Mota, I Cassel, SH Compagno, M Wang, Q Dall'Olio, R Minero, VG
Menotti, Matteo
Ambrogio, C
Cheong, TC
Pighi, C
Mota, I
Cassel, SH
Compagno, M
Wang, Q
Dall'Olio, R
Minero, VG
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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-?. 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.
Authors
Menotti, Matteo
Ambrogio, C
Cheong, TC
Pighi, C
Mota, I
Cassel, SH
Compagno, M
Wang, Q
Dall'Olio, R
Minero, VG
Poggio, T
Sharma, GG
Patrucco, E
Mastini, C
Choudhari, R
Pich, A
Zamo, A
Piva, R
Giliani, S
Mologni, L
Collings, CK
Kadoch, C
Gambacorti-Passerini, C
Notarangelo, LD
Anton, IM
Voena, C
Chiarle, R
Ambrogio, C
Cheong, TC
Pighi, C
Mota, I
Cassel, SH
Compagno, M
Wang, Q
Dall'Olio, R
Minero, VG
Poggio, T
Sharma, GG
Patrucco, E
Mastini, C
Choudhari, R
Pich, A
Zamo, A
Piva, R
Giliani, S
Mologni, L
Collings, CK
Kadoch, C
Gambacorti-Passerini, C
Notarangelo, LD
Anton, IM
Voena, C
Chiarle, R
Description
Date
2018
Publisher
Collections
Keywords
Type
Article
Citation
Menotti 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.