Skip to main content
SpringerLink
Log in

Fc receptor-like 1 (FCRL1) is a novel biomarker for prognosis and a possible therapeutic target in diffuse large B-cell lymphoma

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s lymphoma, which can involve various types of mature B-cells. Considering that the incidence of DLBCL has increased, additional research is required to identify novel and effective prognostic and therapeutic molecules. Fc receptor-like 1 (FCRL1) acts as an activation co-receptor of human B-cells. Aberrant expression of this molecule has been reported in a number of B-cell-related disorders. Moreover, the clinical significance and prognosis value of FCRL1 in DLBCL are not completely identified.

Methods

In this study, the expression levels of FCRL1 were determined in thirty patients with DLBCL and 15 healthy controls (HCs). In addition, the correlation between FCRL1 expressions with clinicopathological variables of DLBCL patients were examined. Then, the potential roles of FCRL1 in proliferation, apoptosis, and cell cycle distribution of B-cells from DLBCL patients were determined using flow cytometry analysis, after knockdown of this marker using retroviral short hairpin RNA interference. Quantitative real time-PCR, western blotting, and enzyme-linked immunosorbent assay were also used to identify the possible effects of FCRL1 knockdown on the expression levels of BCL-2, BID, BAX, intracellular signaling pathway PI3K/p-Akt, and p65 nuclear factor‐kappa B (NF-κB) in the B-cells of DLBCL.

Results

Statistical analysis revealed higher levels of FCRL1 expression in the B-cells of DLBCL patients compared to HCs at both protein and mRNA levels. A positive correlation was observed between the FCRL1 expression and some clinicopathological parameters of DLBCL patients. In addition, FCRL1 knockdown significantly decreased cell proliferation and stimulated apoptosis as well as G1 cell cycle arrest in the B-cells of DLBCL patients. The levels of p65 NF-κB and PI3K/p-Akt expressions were markedly reduced after knockdown of FCRL1 expression.

Conclusions

These results suggested that FCRL1 could be a potential novel biomarker for prognosis and/or a possible effective therapeutic target for treatment of patients with DLBCL.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bowzyk Al-Naeeb A, Ajithkumar T, Behan S, Hodson DJ (2018) Non-Hodgkin lymphoma. BMJ (Clin Res ed) 362:k3204. https://doi.org/10.1136/bmj.k3204

    Article  Google Scholar 

  2. Susanibar-Adaniya S, Barta SK (2021) 2021 Update on Diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and management. Am J Hematol 96:617–629. https://doi.org/10.1002/ajh.26151

    Article  Google Scholar 

  3. Chen B-J, Fend F, Campo E, Quintanilla-Martinez L (2019) Aggressive B-cell lymphomas: from morphology to molecular pathogenesis. Ann Lymphoma. https://doi.org/10.21037/aol.2018.12.02

    Article  Google Scholar 

  4. Frick M, Dörken B, Lenz G (2011) The molecular biology of diffuse large B-cell lymphoma. Ther Adv Hematol 2:369–379. https://doi.org/10.1177/2040620711419001

    Article  CAS  Google Scholar 

  5. Weber T, Schmitz R (2022) Molecular subgroups of diffuse large B cell lymphoma: biology and implications for clinical practice. Curr Oncol Rep 24:13–21. https://doi.org/10.1007/s11912-021-01155-2

    Article  CAS  Google Scholar 

  6. Hunter E, McCord R, Ramadass AS et al (2020) Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies. Transl Med Commun 5:5. https://doi.org/10.1186/s41231-020-00054-1

    Article  Google Scholar 

  7. Mamgain G, Singh PK, Patra P et al (2022) Diffuse large B-cell lymphoma and new insights into its pathobiology and implication in treatment. J Fam Med Prim Care. https://doi.org/10.4103/jfmpc.jfmpc_2432_21

    Article  Google Scholar 

  8. Epperla N, Vaughn JL, Othus M et al (2020) Recent survival trends in diffuse large B-cell lymphoma: have we made any progress beyond rituximab? Cancer Med 9:5519–5525. https://doi.org/10.1002/cam4.3237

    Article  CAS  Google Scholar 

  9. Durmaz M, Visser O, Posthuma EFM et al (2022) Time trends in primary therapy and relative survival of diffuse large B-cell lymphoma by stage: a nationwide, population-based study in the Netherlands, 1989–2018. Blood Cancer J 12:38. https://doi.org/10.1038/s41408-022-00637-1

    Article  Google Scholar 

  10. Sehn LH, Salles G (2021) Diffuse large B-Cell lymphoma. N Engl J Med 384:842–858. https://doi.org/10.1056/NEJMra2027612

    Article  CAS  Google Scholar 

  11. Spinner MA, Advani RH (2022) Current frontline treatment of diffuse large B-Cell lymphoma. Oncology (Williston Park) 36:51–58. https://doi.org/10.46883/2022.25920940

    Article  Google Scholar 

  12. Hatzivassiliou G, Miller I, Takizawa J et al (2001) IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy. Immunity 14:277–289. https://doi.org/10.1016/S1074-7613(01)00109-1

    Article  CAS  Google Scholar 

  13. Davis RS, Wang YH, Kubagawa H, Cooper MD (2001) Identification of a family of Fc receptor homologs with preferential B cell expression. Proc Natl Acad Sci USA 98:9772–9777. https://doi.org/10.1073/pnas.171308498

    Article  CAS  Google Scholar 

  14. Davis RS (2007) Fc receptor-like molecules. Annu Rev Immunol 25:525–560. https://doi.org/10.1146/annurev.immunol.25.022106.141541

    Article  CAS  Google Scholar 

  15. Rostamzadeh D, Kazemi T, Amirghofran Z, Shabani M (2018) Update on Fc Receptor-Like (FCRL) family: new immunoregulatory players in health and diseases. Expert Opin Ther Targets 22:487–502. https://doi.org/10.1080/14728222.2018.1472768

    Article  CAS  Google Scholar 

  16. GGRA E, Leu C-M, Zhang S et al (2007) Fc receptor–like proteins (FCRL): immunomodulators of B cell function. Mechanisms of lymphocyte activation and immune regulation XI. Springer, New York, pp 155–162

    Google Scholar 

  17. Yousefi Z, Sharifzadeh S, Yar-Ahmadi V et al (2019) Fc receptor-like 1 as a promising target for immunotherapeutic interventions of B-cell-related disorders. Biomarker Insights 14:1177271919882351. https://doi.org/10.1177/1177271919882351

    Article  Google Scholar 

  18. Rostamzadeh D, Dabbaghmanesh MH, Shabani M et al (2015) Expression profile of human Fc receptor-like 1, 2, and 4 molecules in peripheral blood mononuclear cells of patients with Hashimoto’s thyroiditis and graves’. Disease 47:693–698. https://doi.org/10.1055/s-0035-1545280

    Article  CAS  Google Scholar 

  19. Yeo L, Lom H, Juarez M et al (2015) Expression of FcRL4 defines a pro-inflammatory, RANKL-producing B cell subset in rheumatoid arthritis. Ann Rheum Dis 74:928–935. https://doi.org/10.1136/annrheumdis-2013-204116

    Article  CAS  Google Scholar 

  20. Baranov KO, Volkova OY, Mechetina LV et al (2012) Expression of human B-Cell specific receptor FCRL1 in healthy individuals and in patients with autoimmune diseases. Mol Biol 46:450–456. https://doi.org/10.1134/S0026893312020045

    Article  CAS  Google Scholar 

  21. Wang K, Pei H, Huang B et al (2012) Overexpression of Fc receptor-like 1 associated with B-cell activation during hepatitis b virus infection. Braz J Med Biol Res 45:1112–1118. https://doi.org/10.1590/S0100-879X2012007500130

    Article  CAS  Google Scholar 

  22. Portugal S, Tipton CM, Sohn H et al (2015) Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function. Elife 4:e07218. https://doi.org/10.7554/eLife.07218.017

    Article  Google Scholar 

  23. Capone M, Bryant JM, Sutkowski N, Haque A (2016) Fc receptor-like proteins in pathophysiology of B-cell disorder. J Clin Cell Immunol. https://doi.org/10.4172/2155-9899.1000427

    Article  Google Scholar 

  24. Ise T, Nagata S, Kreitman RJ et al (2007) Elevation of soluble CD307 (IRTA2/FcRH5) protein in the blood and expression on malignant cells of patients with multiple myeloma, chronic lymphocytic leukemia, and mantle cell lymphoma. Leukemia 21:169. https://doi.org/10.1038/sj.leu.2404445

    Article  CAS  Google Scholar 

  25. Falini B, Agostinelli C, Bigerna B et al (2012) IRTA1 is selectively expressed in nodal and extranodal marginal zone lymphomas. Histopathology 61:930–941. https://doi.org/10.1111/j.1365-2559.2012.04289.x

    Article  Google Scholar 

  26. Li FJ, Ding S, Pan J et al (2008) FCRL2 expression predicts IGHV mutation status and clinical progression in chronic lymphocytic leukemia. Blood 112:179–187. https://doi.org/10.1182/blood-2008-01-131359

    Article  CAS  Google Scholar 

  27. Polson AG, Zheng B, Elkins K et al (2006) Expression pattern of the human FcRH/IRTA receptors in normal tissue and in B-chronic lymphocytic leukemia. Int Immunol 18:1363–1373. https://doi.org/10.1093/intimm/dxl069

    Article  CAS  Google Scholar 

  28. Du X, Nagata S, Ise T et al (2008) FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins. Blood 111:338–343. https://doi.org/10.1182/blood-2007-07-102350

    Article  CAS  Google Scholar 

  29. Masir N, Jones M, Pozzobon M et al (2004) Expression pattern of FCRL (FREB, FcRX) in normal and neoplastic human B cells. Br J Haematol 127:335–343. https://doi.org/10.1111/j.1365-2141.2004.05193.x

    Article  CAS  Google Scholar 

  30. Yousefi Z, Eskandari N (2019) Prognostic significance of Fc receptor-like 1 in patients with chronic lymphocytic leukemia, hairy cell leukemia, and various B-cell non-Hodgkin’s lymphoma. Leuk Res Rep 12:100181. https://doi.org/10.1016/j.lrr.2019.100181

    Article  Google Scholar 

  31. Davis RS, Dennis G, Odom MR et al (2002) Fc receptor homologs: Newest members of a remarkably diverse Fc receptor gene family. Immunol Rev 190:123–136. https://doi.org/10.1034/j.1600-065X.2002.19009.x

    Article  CAS  Google Scholar 

  32. DeLuca JM, Murphy MK, Wang X, Wilson TJ (2021) FCRL1 regulates B cell receptor-induced ERK activation through GRB2. J Immunol (Baltimore, MD: 1950) 207:2688–2698. https://doi.org/10.4049/jimmunol.2100218

    Article  CAS  Google Scholar 

  33. Zhao X, Xie H, Zhao M et al (2019) Fc receptor-like 1 intrinsically recruits c-Abl to enhance B cell activation and function. Sci Adv 5:eaaw0315. https://doi.org/10.1126/sciadv.aaw0315

    Article  CAS  Google Scholar 

  34. Leu C, Davis RS, Gartland LA et al (2017) FcRH1: an activation coreceptor on human B cells. Blood 105:1121–1127. https://doi.org/10.1182/blood-2004-06-2344

    Article  CAS  Google Scholar 

  35. Vallangeon BD, Tyer C, Williams B, Lagoo AS (2016) Improved detection of diffuse large B-cell lymphoma by flow cytometric immunophenotyping: effect of tissue disaggregation method. Cytom B Clin Cytom 90:455–461. https://doi.org/10.1002/cyto.b.21322

    Article  CAS  Google Scholar 

  36. Cunningham RE (2010) Tissue disaggregation. Immunocytochemical methods and protocols. Springer, New York, pp 327–330

    Chapter  Google Scholar 

  37. Chang AY, Chau VW, Landas JA, Pang Y (2017) Preparation of calcium competent Escherichia coli and heat-shock transformation. JEMI Methods 1:22–25

    Google Scholar 

  38. Qureshi HY, Ahmad R, Zafarullah M (2008) High-efficiency transfection of nucleic acids by the modified calcium phosphate precipitation method in chondrocytes. Anal Biochem 382:138–140. https://doi.org/10.1016/j.ab.2008.07.027

    Article  CAS  Google Scholar 

  39. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30:e36–e36. https://doi.org/10.1093/nar/30.9.e36

    Article  Google Scholar 

  40. Pfaffl M (2009) Rest 2009 Software user guide. Qiagen, Hilden, Germany. https://www.gene-quantification.de/rest-2009.html

  41. Frontzek F, Karsten I, Schmitz N, Lenz G (2022) Current options and future perspectives in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma. Ther Adv Hematol 13:20406207221103320. https://doi.org/10.1177/20406207221103321

    Article  CAS  Google Scholar 

  42. Wang L, Li L, Young KH (2020) New agents and regimens for diffuse large B cell lymphoma. J Hematol Oncol 13:175. https://doi.org/10.1186/s13045-020-01011-z

    Article  CAS  Google Scholar 

  43. Lam LT, Davis RE, Pierce J et al (2005) Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin Cancer Res 11:28–40

    Article  CAS  Google Scholar 

  44. Lam LT, Wright G, Davis RE et al (2008) Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor- B pathways in subtypes of diffuse large B-cell lymphoma. Cytokine 111:3701–3713. https://doi.org/10.1182/blood-2007-09-111948.The

    Article  CAS  Google Scholar 

  45. Lodhi N, Tun M, Nagpal P et al (2020) Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine. Oncotarget 11:4045–4073. https://doi.org/10.18632/oncotarget.27785

    Article  Google Scholar 

  46. Bai D, Ueno L, Vogt P (2009) Akt-mediated regulation of NFkB for the oncogenicity of PI3K and Akt. Int J Cancer 125:2863–2870. https://doi.org/10.1002/ijc.24748.Akt-mediated

    Article  CAS  Google Scholar 

  47. Davis RE, Brown KD, Siebenlist U, Staudt LM (2001) Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194:1861–1874. https://doi.org/10.1084/jem.194.12.1861

    Article  CAS  Google Scholar 

  48. Schatz JH (2011) Targeting the PI3K/AKT/mTOR pathway in non-Hodgkin’s lymphoma: results, biology, and development strategies. Curr Oncol Rep 13:398–406. https://doi.org/10.1007/s11912-011-0187-7

    Article  CAS  Google Scholar 

  49. Staff PONE (2014) Correction: cross-talk between NFkB and the PI3-Kinase/AKT pathway can be targeted in primary effusion lymphoma (PEL) cell lines for efficient apoptosis. PLoS ONE 9:e92484. https://doi.org/10.1371/journal.pone.0092484

    Article  CAS  Google Scholar 

  50. Pavan A, Spina M, Canzonieri V et al (2008) Recent prognostic factors in diffuse large B-cell lymphoma indicate NF-κB pathway as a target for new therapeutic strategies. Leuk Lymphoma 49:2048–2058. https://doi.org/10.1080/10428190802444176

    Article  CAS  Google Scholar 

  51. Wang J, Xu-Monette ZY, Jabbar KJ et al (2017) AKT hyperactivation and the potential of AKT-targeted therapy in diffuse large B-cell lymphoma. Am J Pathol 187:1700–1716. https://doi.org/10.1016/j.ajpath.2017.04.009

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The present study was supported by Isfahan University of Medical Sciences as a PhD Thesis.

Funding

This study was funded by Isfahan University of Medical Sciences (grant number: 394608).

Author information

Authors and Affiliations

  1. School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran

    Zahra Yousefi

  2. Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran

    Sedigheh Sharifzadeh & Farahnaz Zare

  3. Diagnostic Laboratory Sciences and Technology Research Center, Faculty of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran

    Sedigheh Sharifzadeh & Farahnaz Zare

  4. Department of Immunology, Isfahan University of Medical Sciences, Isfahan, Iran

    Nahid Eskandari

Authors
  1. Zahra Yousefi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sedigheh Sharifzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Farahnaz Zare
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nahid Eskandari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nahid Eskandari.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interests.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards outlined by the ethics committee of Isfahan University of Medical Sciences (ID: IR.MUI.REC.1394.3.608) as well as the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all the participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

11033_2022_8104_MOESM1_ESM.jpg

Supplementary material 1 (JPG 116 kb). Supplementary Fig. 1. Gating strategy and flow cytometric analysis of FCRL1 protein expression (A) in B-cells of one healthy individual (B) and malignant/ lymphoma B-cells of one patients with DLBCL

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yousefi, Z., Sharifzadeh, S., Zare, F. et al. Fc receptor-like 1 (FCRL1) is a novel biomarker for prognosis and a possible therapeutic target in diffuse large B-cell lymphoma. Mol Biol Rep 50, 1133–1145 (2023). https://doi.org/10.1007/s11033-022-08104-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-08104-7

Keywords

Search

Navigation