Original Article | Published:

Lymphoma

Recurrent activating mutations of CD28 in peripheral T-cell lymphomas

Leukemia volume 30, pages 10621070 (2016) | Download Citation

Abstract

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T-cell neoplasms with a poor prognosis. Recently, mutations in TET2 and other epigenetic modifiers as well as RHOA have been identified in these diseases, particularly in angioimmunoblastic T-cell lymphoma (AITL). CD28 is the major co-stimulatory receptor in T cells which, upon binding ligand, induces sustained T-cell proliferation and cytokine production when combined with T-cell receptor stimulation. We have identified recurrent mutations in CD28 in PTCLs. Two residues—D124 and T195—were recurrently mutated in 11.3% of cases of AITL and in one case of PTCL, not otherwise specified (PTCL-NOS). Surface plasmon resonance analysis of mutations at these residues with predicted differential partner interactions showed increased affinity for ligand CD86 (residue D124) and increased affinity for intracellular adaptor proteins GRB2 and GADS/GRAP2 (residue T195). Molecular modeling studies on each of these mutations suggested how these mutants result in increased affinities. We found increased transcription of the CD28-responsive genes CD226 and TNFA in cells expressing the T195P mutant in response to CD3 and CD86 co-stimulation and increased downstream activation of NF-κB by both D124V and T195P mutants, suggesting a potential therapeutic target in CD28-mutated PTCLs.

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Acknowledgements

We thank R Redder and Dr A Dhar and J Eudy of the UNMC sequencing core; V Smith and Dr P Hexley of the UNMC flow cytometry core; and L Brown, N Feng and S Hsueh of the COH Analytical Cytometry Core. We would like to thank Elizabeth Chavez at BCCA for performing the TSCA experiment. Thanks to Dr Françoise Berger of Université Lyon 1 for contributing several samples to this study. WCC is supported by NCI SPECS II 5 UO1 CA157581-01, NCI SPORE 1P50CA 136411-01 01A1 PP-4 and City of Hope internal funds; JI is supported by the Lymphoma Research Foundation (F-263549), the Leukemia and Lymphoma Society (TRP-6129-04), the UNMC Clinical-Translational Research Scholars Program, and the NCI Eppley Cancer Center Support Grant P30CA036727. AM is supported by the Dr Mildred-Scheel Cancer Foundation and the Michael Smith Foundation for Health Research. Partial support is from NCI Eppley Cancer Center Support Grant P30CA036727, National Center for Research Resources 5P20RR016469, and National Institute for General Medical Science 8P20GM103427 to GB. The University of Nebraska DNA Sequencing Core receives partial support from the National Center for Research Resources (1S10RR027754-01, 5P20RR016469, RR018788-08) and the National Institute for General Medical Science (8P20GM103427, GM103471-09). Research reported in this publication included work performed in the City of Hope Analytical Cytometry Core supported by the NCI and NIH under award number P30CA33572. This publication’s contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH, FDA or NIGMS. WCC is the recipient of a Lymphoma SPORE Developmental Research Award (P50 CA107399).

Author contributions

JR designed and performed research, analyzed data and wrote the manuscript. SG designed and performed research. YL and CS designed research. JH and SD designed and performed SPR analysis. AB, CL, AM, TH and AC performed research. PS and GB designed and performed molecular modeling analysis. WZ, QG, CW, SH and WX analyzed sequencing data. AR, RG, KF, TG, DW and JV provided clinical samples and edited the manuscript. TM and JI designed research, analyzed data and edited and approved the final version of the manuscript. WCC supervised and designed research, and edited and approved the final version of the manuscript.

Author information

Author notes

    • J Rohr
    •  & S Guo

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    • J Rohr
    • , A Bouska
    • , C Lachel
    • , W Zhang
    • , C Wang
    • , A Cannon
    • , T Heavican
    • , K Fu
    • , T C Greiner
    •  & J Iqbal
  2. Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA

    • J Rohr
    • , Y Li
    • , Q Gong
    • , C Wang
    • , D D Weisenburger
    • , T McKeithan
    •  & W C Chan
  3. Department of Pathology, Xi Jing Hospital, Fourth Military Medical University, Xi’an, Shaan Xi Province, China

    • S Guo
  4. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    • J Huo
    •  & S Davis
  5. Internal Medicine Residency Program, Florida Atlantic University College of Medicine, Boca Raton, FL, USA

    • P D Simone
  6. School of Medicine, Shandong University, Jinan, China

    • C Wang
  7. Department for Lymphoid Cancer Research, Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada

    • A Mottok
    • , S Hung
    • , R Gascoyne
    •  & C Steidl
  8. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    • A Mottok
    • , S Hung
    • , R Gascoyne
    •  & C Steidl
  9. Institute of Pathology and Comprehensive Cancer Center Mainfranken (CCC MF), University of Wuerzburg, Wuerzburg, Germany

    • A Rosenwald
  10. Department of Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    • J M Vose
  11. National Institutes of Health, Bethesda, MD, USA

    • L M Staudt
  12. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, Food and Drug Administration, Washington, DC, USA

    • W Xiao
  13. Eppley Institute for Cancer Research and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    • G E O Borgstahl

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Competing interests

KF is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents and Royalties.

Corresponding authors

Correspondence to J Iqbal or W C Chan.

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DOI

https://doi.org/10.1038/leu.2015.357

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

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