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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  1. 1.

    Sullivan, K. E., Mullen, C. A., Blaese, R. M. & Winkelstein, J. A. A multiinstitutional survey of the Wiskott–Aldrich syndrome. J. Pediatr. 125, 876–885 (1994).

  2. 2.

    Anton, I. M. et al. WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation. Immunity 16, 193–204 (2002).

  3. 3.

    de la Fuente, M. A. et al. WIP is a chaperone for Wiskott–Aldrich syndrome protein (WASP). Proc. Natl Acad. Sci. USA 104, 926–931 (2007).

  4. 4.

    Ramesh, N. & Geha, R. Recent advances in the biology of WASP and WIP. Immunol. Res. 44, 99–111 (2009).

  5. 5.

    Ramesh, N., Anton, I. M., Hartwig, J. H. & Geha, R. S. WIP, a protein associated with wiskott-aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. Proc. Natl Acad. Sci. USA 94, 14671–14676 (1997).

  6. 6.

    Abdul-Manan, N. et al. Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott–Aldrich syndrome’ protein. Nature 399, 379–383 (1999).

  7. 7.

    Thrasher, A. J. & Burns, S. O. WASP: a key immunological multitasker. Nat. Rev. Immunol. 10, 182–192 (2010).

  8. 8.

    Massaad, M. J., Ramesh, N. & Geha, R. S. Wiskott–Aldrich syndrome: a comprehensive review. Ann. N. Y. Acad. Sci. 1285, 26–43 (2013).

  9. 9.

    Snapper, S. B. et al. Wiskott–Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9, 81–91 (1998).

  10. 10.

    Ochs, H. D. & Thrasher, A. J. The Wiskott–Aldrich syndrome. J. Allergy Clin. Immunol. 117, 725–738 (2006). quiz 739.

  11. 11.

    Recher, M. et al. B cell-intrinsic deficiency of the Wiskott–Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice. Blood 119, 2819–2828 (2012).

  12. 12.

    Boddicker, R. L., Razidlo, G. L. & Feldman, A. L. Genetic alterations affecting GTPases and T-cell receptor signaling in peripheral T-cell lymphomas. Small GTPases 29, 1–7 (2016).

  13. 13.

    Scarfo, I. et al. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. Blood 127, 221–232 (2016).

  14. 14.

    Crescenzo, R. et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 27, 516–532 (2015).

  15. 15.

    Parrilla Castellar, E. R. et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood 124, 1473–1480 (2014).

  16. 16.

    Werner, M. T., Zhao, C., Zhang, Q. & Wasik, M. A. Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target. Blood 129, 823–831 (2017).

  17. 17.

    Yoo, H. Y. et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 371–375 (2014).

  18. 18.

    Sakata-Yanagimoto, M. et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 171–175 (2014).

  19. 19.

    Palomero, T. et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat. Genet. 46, 166–170 (2014).

  20. 20.

    Abate, F. et al. Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc. Natl Acad. Sci. USA 114, 764–769 (2017).

  21. 21.

    Ambrogio, C. et al. The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation. Cancer Res. 68, 8899–8907 (2008).

  22. 22.

    Colomba, A. et al. Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas. Oncogene 27, 2728–2736 (2008).

  23. 23.

    Choudhari, R. et al. Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice. Blood 127, 1297–1306 (2016).

  24. 24.

    Swerdlow, S. H. et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127, 2375–2390 (2016).

  25. 25.

    Chiarle, R. et al. NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. Blood 101, 1919–1927 (2003).

  26. 26.

    Lanzi, G. et al. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J. Exp. Med. 209, 29–34 (2012).

  27. 27.

    Al-Mousa, H. et al. Hematopoietic stem cell transplantation corrects WIP deficiency. J. Allergy Clin. Immunol. 139, 1039–1040 e1034 (2017).

  28. 28.

    Notarangelo, L. D., Notarangelo, L. D. & Ochs, H. D. WASP and the phenotypic range associated with deficiency. Curr. Opin. Allergy. Clin. Immunol. 5, 485–490 (2005).

  29. 29.

    Hill, C. S., Wynne, J. & Treisman, R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell 81, 1159–1170 (1995).

  30. 30.

    Ambrogio, C. et al. NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells. Cancer Res. 69, 8611–8619 (2009).

  31. 31.

    Hassler, M. R. et al. Insights into the pathogenesis of anaplastic large-cell lymphoma through genome-wide DNA methylation profiling. Cell Rep. 17, 596–608 (2016).

  32. 32.

    Piva, R. et al. Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas. Blood 107, 689–697 (2006).

  33. 33.

    Gambacorti Passerini, C. et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J. Natl Cancer. Inst. 106, djt378 (2014).

  34. 34.

    Hrustanovic, G. et al. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat. Med. 21, 1038–1047 (2015).

  35. 35.

    Rivers, E. & Thrasher, A. J. Wiskott–Aldrich syndrome protein: emerging mechanisms in immunity. Eur. J. Immunol. 47, 1857–1866 (2017).

  36. 36.

    Chiarle, R. et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat. Med. 11, 623–629 (2005).

  37. 37.

    Watanabe, Y. et al. T-cell receptor ligation causes Wiskott–Aldrich syndrome protein degradation and F-actin assembly downregulation. J. Allergy Clin. Immunol. 132, 648–655 e641 (2013).

  38. 38.

    Murga-Zamalloa, C. A. et al. NPM-ALK phosphorylates WASp Y102 and contributes to oncogenesis of anaplastic large cell lymphoma. Oncogene 36, 2085–2094 (2017).

  39. 39.

    Zhang, J. et al. Intersectin 2 controls actin cap formation and meiotic division in mouse oocytes through the Cdc42 pathway. FASEB J 31, 4277–4285 (2017).

  40. 40.

    McGavin, M. K. et al. The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis. J. Exp. Med. 194, 1777–1787 (2001).

  41. 41.

    Wu, X. et al. Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin. Genes Dev. 20, 571–585 (2006).

  42. 42.

    Facchetti, F. et al. Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott–Aldrich syndrome. J. Pathol. 185, 99–107 (1998).

  43. 43.

    Martinengo, C. et al. ALK-dependent control of hypoxia inducible factors mediates tumor growth and metastasis. Cancer Res. 74, 6094–106 (2014).

  44. 44.

    Piva, R. et al. Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes. J. Clin. Invest. 116, 3171–3182 (2006).

  45. 45.

    Ceccon, M. et al. Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency. Oncogene 35, 3854–3865 (2016).

  46. 46.

    Orlando, D. A. et al. Quantitative ChIP-seq normalization reveals global modulation of the epigenome. Cell reports 9, 1163–1170 (2014).

  47. 47.

    Mansour, M. R. et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373–1377 (2014).

  48. 48.

    Manser, M. et al. ELF-MF exposure affects the robustness of epigenetic programming during granulopoiesis. Sci. Rep. 7, 43345 (2017).

  49. 49.

    Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).

  50. 50.

    Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).

  51. 51.

    Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

  52. 52.

    Kuhn, R. M., Haussler, D. & Kent, W. J. The UCSC genome browser and associated tools. Brief. Bioinform. 14, 144–161 (2013).

  53. 53.

    Zhang, Y. et al. Model-based analysis of ChIP-seq (MACS). Genome. Biol. 9, R137 (2008).

  54. 54.

    Shen, L., Shao, N., Liu, X. & Nestler, E. ngs.plot: quick mining and visualization of next-generation sequencing data by integrating genomic databases. BMC Genomics 15, 284 (2014).

  55. 55.

    Ambrogio, C. et al. Kras dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell 172, 857–868 e815 (2018).

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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.


  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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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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