Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Medicine volume 25, pages 130–140 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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).

References

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

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

  1. Matteo Menotti

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

  2. 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

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

Authors and 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

Authors
  1. Matteo Menotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiara Ambrogio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taek-Chin Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chiara Pighi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ines Mota
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seth H. Cassel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mara Compagno
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Riccardo Dall’Olio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Valerio G. Minero
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Teresa Poggio
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Geeta Geeta Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Enrico Patrucco
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Cristina Mastini
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ramesh Choudhari
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Achille Pich
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Alberto Zamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Roberto Piva
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Silvia Giliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Luca Mologni
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Clayton K. Collings
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Cigall Kadoch
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Carlo Gambacorti-Passerini
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Luigi D. Notarangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Ines M. Anton
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Claudia Voena
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Roberto Chiarle
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Claudia Voena or Roberto Chiarle.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Table 1

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing