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

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.

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Fig. 1: WASP and WIP are selectively down-regulated in ALCL.
Fig. 2: WASP is an oncosuppressor in ALK+ T cell lymphoma.
Fig. 3: CDC42 and ERK hyperactivation in WASP-deficient lymphoma.
Fig. 4: CDC42 is essential for the survival of WASP-deficient lymphoma cells.
Fig. 5: Oncogenic ALK down-regulates WASP and WIP expression through STAT3 and C/EBPβ.
Fig. 6: MAPK pathway is a therapeutic vulnerability in WASP-deficient cells.

Data availability

The Gene Expression Omnibus repository accession number for the gene expression profiling data from wild type and Wasp/− mice is GSE102889 (token: gzelisgodjkdxqt); and for ChIP-seq data, the accession number is GSE117164 (token: chupqsgklxivtox). Gene-expression profiling data for human T cell lymphoma have been deposited with Gene Expression Omnibus repository accession number GSE65823 (ref. 13).

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Acknowledgements

We thank M.S. Scalzo and D. Corino for technical assistance, and B. Castella for providing purified human T cells. The work has been supported by grant no. FP7 ERC-2009-StG (Proposal No. 242965—‘Lunely’) (R.C.) grant no. R01 CA196703-01 (R.C.); AIRC grant no. MFAG (C.A. and M.C.); National Research Foundation of Korea (NRF) fellowship 2016R1A6A3A03006840 (T-C.C.); Bando Giovani Ricercatori grant no. 2009-GR 1603126 (M.C.); MINECO/FEDER grant no. SAF2015–70368-R and Fundación Ramón Areces (I.M.A.); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (L.D.N.); and award no. T32GM007753 from the National Institute of General Medical Sciences (S.H.C.) (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health); and in part by awards from the National Institutes of Health DP2 New Innovator award no. 1DP2CA195762-01 (C.K.); the American Cancer Society Research Scholar award no. RSG-14-051-01-DMC and the Pew-Stewart Scholars in Cancer Research Grant (C.K.); and the European Union Horizon 2020 Marie Sklodowska-Curie Innovative Training Network Grant award no. 675712 for the European Research Initiative for ALK-Related Malignancies (G.G.S., I.M., C.GP. and R.C.).

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M.M., C.A., T.-C.C., C.P., I.M., S.H.C., M.C., R.D., T.P., E.P., C.M. amd C.V. performed experiments. M.M., V.M., C.V. and R. Choudhari performed mice experiments. Q.W. and C.K.C. performed bioinformatics analysis. A.P. analyzed data. R.P. provided gene expression data on lymphoma samples. C.K. provided reagents for ChIP-seq. S.G. and L.G.N. provided WAS patient samples and analyzed data. G.G.S., L.M. and C.G.-P. provided sequencing data on patients with ALCL. A.Z. provided lymphoma cases. I.M.A. contributed mouse strains and analyzed data. C.V. and R. Chiarle conceived and analyzed the experiments. M.M., C.V. and R. Chiarle wrote the manuscript.

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Correspondence to Claudia Voena or Roberto Chiarle.

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Menotti, M., Ambrogio, C., Cheong, TC. et al. Wiskott–Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma. Nat Med 25, 130–140 (2019). https://doi.org/10.1038/s41591-018-0262-9

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