Skip to main content

Advertisement

SpringerLink
Log in

RNA and protein expression of herpesvirus entry mediator (HVEM) is associated with molecular markers, immunity-related pathways and relapse-free survival of patients with AML

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Immune checkpoint molecules are highly relevant as potential prognostic markers and therapeutic targets in malignant diseases. HVEM belongs to the TNF receptor family and provides stimulatory as well as inhibitory signals depending on the ligand. Abnormal HVEM expression has been described in various malignancies, but the role in AML is unknown. Here we report extensive data on HVEM surface protein expression analyzed by flow cytometry on bone marrow leukemic cells of 169 AML patients at diagnosis. An independent cohort of 512 AML patients was analyzed for HVEM mRNA expression in bone marrow samples by Affymetrix microarrays. Consistently for both cohorts and methods, we show that HVEM was differentially expressed and that expression levels were associated with defined genetic markers. HVEM expression was lower in cases with FLT3-ITD (p = 0.001, p < 0.001), with mutations in NPM1 (p = 0.001, p < 0.001) or with the combination of NPM1 mutation and FLT3 wild type (p = 0.049, p = 0.050), while a biallelic mutation in CEBPA correlated positively with higher HVEM expression (p = 0.015, p < 0.001). In a differential gene expression analysis, we found 13 genes including HOXA9, MEIS1 and MN1 that were closely associated with HVEM expression. Besides, four gene sets closely linked to immunity were enriched in HVEM high samples. Finally, high expression of HVEM was associated with a trend toward longer relapse-free survival. The results of this study provide new information on the potential significance of HVEM in AML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AML:

Acute myeloid leukemia

AML-CG:

AML Cooperative Group

BM:

Bone marrow

CEBPA:

CCAAT/enhancer-binding protein alpha

CR:

Complete remission

ELN:

European LeukemiaNet

FLT3:

Fms-like tyrosine kinase 3

GSEA:

Gene set enrichment analysis

HVEM:

Herpesvirus entry mediator

Limma:

Linear Models for Microarray Data

MFI:

Mean fluorescence intensity

MRC:

Medical Research Council

NPM1:

Nucleophosmin

OS:

Overall survival

RFS:

Relapse-free survival

sAML:

Secondary AML

SCT:

Stem cell transplantation

SFI:

Specific fluorescence intensity

TNFR:

Tumor necrosis factor receptor

References

  1. Pasero C, Speiser DE, Derré L, Olive D (2012) The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy. Curr Opin Pharmacol 12:478–485

    Article  CAS  PubMed  Google Scholar 

  2. Morel Y, Truneh A, Sweet RW, Olive D, Costello RT (2001) The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 167:2479–2486

    Article  CAS  PubMed  Google Scholar 

  3. Duhen T, Pasero C, Mallet F, Barbarat B, Olive D, Costello RT (2004) LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell-dependent B cell terminal differentiation. Eur J Immunol 34:3534–3541

    Article  CAS  PubMed  Google Scholar 

  4. Murphy TL, Murphy KM (2010) Slow down and survive: enigmatic immunoregulation by BTLA and HVEM. Annu Rev Immunol 28:389–411

    Article  CAS  PubMed  Google Scholar 

  5. Wang Y, Subudhi SK, Anders RA, Lo J, Sun Y, Blink S, Wang Y, Wang J, Liu X, Mink K, Degrandi D, Pfeffer K, Fu YX (2005) The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses. J Clin Invest 115:711–717

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. del Rio ML, Lucas CL, Buhler L, Rayat G, Rodriguez-Barbosa JI (2010) HVEM/LIGHT/BTLA/CD160 cosignaling pathways as targets for immune regulation. J Leukoc Biol 87:223–235

    Article  PubMed  Google Scholar 

  7. Costello RT, Mallet F, Barbarat B, De Colella JMS, Sainty D, Sweet RW, Truneh A, Olive D (2003) Stimulation of non-Hodgkin’s lymphoma via HVEM: an alternate and safe way to increase Fas-induced apoptosis and improve tumor immunogenicity. Leukemia 17:2500–2507

    Article  CAS  PubMed  Google Scholar 

  8. Derré L, Rivals JP, Jandus C, Pastor S, Rimoldi D, Romero P, Michielin O, Olive D, Speiser DE (2010) BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J Clin Invest 120:157–167

    Article  PubMed Central  PubMed  Google Scholar 

  9. Migita K, Sho M, Shimada K, Yasuda S, Yamato I, Takayama T, Matsumoto S, Wakatsuki K, Hotta K, Tanaka T, Ito M, Konishi N, Nakajima Y (2014) Significant involvement of herpesvirus entry mediator in human esophageal squamous cell carcinoma. Cancer 120:808–817

    Article  CAS  PubMed  Google Scholar 

  10. Hokuto D, Sho M, Yamato I, Yasuda S, Obara S, Nomi T, Nakajima Y (2015) Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma. Eur J Cancer 51:157–165

    Article  CAS  PubMed  Google Scholar 

  11. Inoue T, Sho M, Yasuda S, Nishiwada S, Nakamura S, Ueda T, Nishigori N, Kawasaki K, Obara S, Nakamoto T, Koyama F, Fujii H, Nakajima Y (2015) HVEM expression contributes to tumor progression and prognosis in human colorectal cancer. Anticancer Res 35:1361–1367

    PubMed  Google Scholar 

  12. Pasero C, Barbarat B, Just-Landi S, Bernard A, Aurran-Schleinitz T, Rey J, Eldering E, Truneh A, Costello RT, Olive D (2009) A role for HVEM, but not lymphotoxin-beta receptor, in LIGHT-induced tumor cell death and chemokine production. Eur J Immunol 39:2502–2514

    Article  CAS  PubMed  Google Scholar 

  13. Hobo W, Norde WJ, Schaap N, Fredrix H, Maas F, Schellens K, Falkenburg JH, Korman AJ, Olive D, van der Voort R, Dolstra H (2012) B and T lymphocyte attenuator mediates inhibition of tumor-reactive CD8+ T cells in patients after allogeneic stem cell transplantation. J Immunol 189:39–49

    Article  CAS  PubMed  Google Scholar 

  14. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK, National Cancer Research Institute Adult Leukaemia Working Group (2010) Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354–365

    Article  CAS  PubMed  Google Scholar 

  15. Li Z, Herold T, He C, Valk PJ, Chen P, Jurinovic V, Mansmann U, Radmacher MD, Maharry KS, Sun M, Yang X, Huang H, Jiang X, Sauerland MC, Büchner T, Hiddemann W, Elkahloun A, Neilly MB, Zhang Y, Larson RA et al (2013) Identification of a 24-gene prognostic signature that improves the European LeukemiaNet risk classification of acute myeloid leukemia: an international collaborative study. J Clin Oncol 31:1172–1181

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47

    Article  PubMed Central  PubMed  Google Scholar 

  17. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Lawrence HJ, Rozenfeld S, Cruz C, Matsukuma K, Kwong A, Kömüves L, Buchberg AM, Largman C (1999) Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13:1993–1999

    Article  CAS  PubMed  Google Scholar 

  19. Zhao P, Tan L, Ruan J, Wei XP, Zheng Y, Zheng LX, Jiang WQ, Fang WJ (2015) Aberrant expression of HOXA5 and HOXA9 in AML. Asian Pac J Cancer Prev 16:3941–3944

    Article  PubMed  Google Scholar 

  20. Li Z, Zhang Z, Li Y, Arnovitz S, Chen P, Huang H, Jiang X, Hong GM, Kunjamma RB, Ren H, He C, Wang CZ, Elkahloun AG, Valk PJ, Döhner K, Neilly MB, Bullinger L, Delwel R, Löwenberg B, Liu PP et al (2013) PBX3 is an important cofactor of HOXA9 in leukemogenesis. Blood 121:1422–1431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Metzeler KH, Dufour A, Benthaus T, Hummel M, Sauerland MC, Heinecke A, Berdel WE, Büchner T, Wörmann B, Mansmann U, Braess J, Spiekermann K, Hiddemann W, Buske C, Bohlander SK (2009) ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays. J Clin Oncol 27:5031–5038

    Article  CAS  PubMed  Google Scholar 

  22. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD, LeukemiaNet European (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:453–474

    Article  PubMed  Google Scholar 

  23. Pasero C, Olive D (2013) Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti-tumor immunity. Immunol Lett 151:71–75

    Article  CAS  PubMed  Google Scholar 

  24. Lichtenegger FS, Schnorfeil FM, Hiddemann W, Subklewe M (2013) Current strategies in immunotherapy for acute myeloid leukemia. Immunotherapy 5:63–78

    Article  CAS  PubMed  Google Scholar 

  25. Lichtenegger FS, Krupka C, Köhnke T, Subklewe M (2015) Immunotherapy for acute myeloid leukemia. Semin Hematol 52:207–214

    Article  CAS  PubMed  Google Scholar 

  26. Zhong RK, Loken M, Lane TA, Ball ED (2006) CTLA-4 blockade by a human MAb enhances the capacity of AML-derived DC to induce T-cell responses against AML cells in an autologous culture system. Cytotherapy 8:3–12

    Article  CAS  PubMed  Google Scholar 

  27. Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED (2009) CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113:1581–1588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A (2008) Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 14:3044–3051

    Article  CAS  PubMed  Google Scholar 

  29. Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR (2010) Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood 116:2484–2493

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK, Blazar BR (2011) Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117:4501–4510

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med 5:200ra116

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Maria Sauerland from the Institute for Biometrics and Clinical Research at the Westfälische Wilhelms-Universität Münster and all doctors of the participating centers for the recruitment of patients and help with acquisition of the clinical data; Elke Habben, Karin Hecht, Sabine Reinkunz and Ewelina Zientara for their excellent technical assistance; and the patients for providing the research samples used in this study. The work was supported by funds from BayImmuNet, the Bavarian Immunotherapy Network (http://www.bayimmunet.de), and by a Metiphys fellowship of the Medical Faculty of the Ludwig-Maximilian Universität München to Felix S. Lichtenegger.

Author contributions

Marion Subklewe was the principal investigator and takes primary responsibility for the paper. Thomas Büchner, Wolfgang E. Berdel, Bernhard J. Wörmann and Wolfgang Hiddemann were principle investigators of the AML-CG 99 trial and recruited the patients for this analysis. Karsten Spiekermann and Stephanie Schneider provided the morphological, cytogenetic and molecular characterization of the patients. Tobias Herold provided the mRNA expression data and their statistical analysis. Felix S. Lichtenegger, Isabell Kondla, Michael Krempasky and Anna L. Weber collected and analyzed the data. Felix S. Lichtenegger and Marion Subklewe coordinated the research and wrote the manuscript.

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany

    Felix S. Lichtenegger, Isabell Kondla, Michael Krempasky, Anna L. Weber, Tobias Herold, Christina Krupka, Karsten Spiekermann, Stephanie Schneider, Wolfgang Hiddemann & Marion Subklewe

  2. Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, Munich, Germany

    Felix S. Lichtenegger, Isabell Kondla, Michael Krempasky, Anna L. Weber, Christina Krupka & Marion Subklewe

  3. Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Universität München, Munich, Germany

    Felix S. Lichtenegger

  4. Clinical Cooperation Group Pathogenesis of Acute Leukemia, Helmholtz Zentrum München, Munich, Germany

    Tobias Herold, Karsten Spiekermann & Wolfgang Hiddemann

  5. Department of Medicine A, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Thomas Büchner & Wolfgang E. Berdel

  6. German Society of Hematology and Oncology, Berlin, Germany

    Bernhard J. Wörmann

Authors
  1. Felix S. Lichtenegger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isabell Kondla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Krempasky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna L. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tobias Herold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christina Krupka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karsten Spiekermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephanie Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas Büchner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wolfgang E. Berdel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bernhard J. Wörmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wolfgang Hiddemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marion Subklewe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Felix S. Lichtenegger.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 797 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lichtenegger, F.S., Kondla, I., Krempasky, M. et al. RNA and protein expression of herpesvirus entry mediator (HVEM) is associated with molecular markers, immunity-related pathways and relapse-free survival of patients with AML. Cancer Immunol Immunother 64, 1505–1515 (2015). https://doi.org/10.1007/s00262-015-1755-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-015-1755-8

Keywords

Search

Navigation