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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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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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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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.).

Author information

Author notes

    • Matteo Menotti

    Present address: Cell Signalling Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK

    • Ramesh Choudhari

    Present address: 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

  1. These authors contributed equally: Chiara Ambrogio, Taek-Chin Cheong.

Affiliations

  1. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy

    • Matteo Menotti
    • , Chiara Pighi
    • , Ines Mota
    • , Mara Compagno
    • , Riccardo Dall’Olio
    • , Valerio G. Minero
    • , Teresa Poggio
    • , Enrico Patrucco
    • , Cristina Mastini
    • , Ramesh Choudhari
    • , Achille Pich
    • , Roberto Piva
    • , Claudia Voena
    •  & Roberto Chiarle
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Chiara Ambrogio
  3. Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    • Taek-Chin Cheong
    • , Chiara Pighi
    • , Mara Compagno
    • , Qi Wang
    •  & Roberto Chiarle
  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    • Seth H. Cassel
    • , Clayton K. Collings
    •  & Cigall Kadoch
  5. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Seth H. Cassel
    • , Clayton K. Collings
    •  & Cigall Kadoch
  6. Biomedical and Biological Sciences Program, Harvard Medical School, Boston, MA, USA

    • Seth H. Cassel
  7. Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA

    • Seth H. Cassel
  8. School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy

    • Geeta Geeta Sharma
    • , Luca Mologni
    •  & Carlo Gambacorti-Passerini
  9. Department of Oncology, University of Torino, Torino, Italy

    • Alberto Zamo
  10. Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    • Silvia Giliani
  11. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    • Luigi D. Notarangelo
  12. Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain

    • Ines M. Anton

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Contributions

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.

Competing Interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Claudia Voena or Roberto Chiarle.

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https://doi.org/10.1038/s41591-018-0262-9