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:

CXCR4 overexpression in chronic lymphocytic leukemia associates with poorer prognosis: A prospective, single-center, observational study

Genes & Immunity volume 25, pages 117–123 (2024)Cite this article

Subjects

Abstract

Controversial data have been reported on the prognostic value of C-X-C motif chemokine receptor 4 (CXCR4) in chronic lymphocytic leukemia (CLL). This prospective, single-center, observational study aimed to evaluate the role of CXCR4 in the pathophysiology of CLL and its prognostic role. A total of 158 patients of CLL were enrolled, and CXCR4 expression on CLL cells was detected by flow cytometry (FCM) at initial diagnosis. The patients were divided into 2 groups according to the CXCR4 mean fluorescence intensity (MFI) median. Also, four patient specimens from the CXCR4low and CXCR4high groups were selected for RNASeq analysis. The progression-free survival (PFS) of CLL patients in the CXCR4high group was significantly shorter than the CXCR4low group, with a median follow-up time of 27 months (log-rank P < 0.001). Moreover, CXCR4 overexpression (MFI > 3376) was an independent marker of poor PFS in CLL patients (P < 0.001). Analysis of RNASeq results revealed that CXCR4 plays an important role in the migration of CLL. Collectively, CXCR4 expression levels on leukemia cells can be detected rapidly by FCM. CXCR4 overexpression was significantly associated with poorer prognosis in CLL patients within a shorter follow-up time.

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: The mean fluorescence intensity (MFI) of CXCR4 expression.
Fig. 2: The prognostic impact of the MFI of CXCR4 expression in CLL patients.
Fig. 3: CXCR4-related gene enrichment analysis.

Similar content being viewed by others

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request. RNAseq data is deposited in NCBI’s Gene Expression Omnibus (GEO) and is accessible through GEO Series accession number: GSE254015.

References

  1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N. Engl J Med. 2005;352:804–15.

    Article  CAS  PubMed  Google Scholar 

  2. Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci USA. 1999;96:5215–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Walenkamp AME, Lapa C, Herrmann K, Wester HJ. CXCR4 ligands: The next big hit? J Nucl Med. 2017;58:77s–82s.

    Article  CAS  PubMed  Google Scholar 

  4. Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood. 1999;94:3658–67.

    Article  CAS  PubMed  Google Scholar 

  5. Binsky I, Haran M, Starlets D, Gore Y, Lantner F, Harpaz N, et al. IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival. Proc Natl Acad Sci USA. 2007;104:13408–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gore Y, Starlets D, Maharshak N, Becker-Herman S, Kaneyuki U, Leng L, et al. Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex. J Biol Chem. 2008;283:2784–92.

    Article  CAS  PubMed  Google Scholar 

  7. Campbell JJ, Hedrick J, Zlotnik A, Siani MA, Thompson DA, Butcher EC. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science. 1998;279:381–4.

    Article  CAS  PubMed  Google Scholar 

  8. Pawig L, Klasen C, Weber C, Bernhagen J, Noels H. Diversity and inter-connections in the CXCR4 Chemokine receptor/ligand family: molecular perspectives. Front Immunol. 2015;6:429.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Andritsos L, Byrd J, Hewes B, Kipps T, Johns D, Burger J. Preliminary results from a phase i dose escalation study to determine the maximum tolerated dose of plerixafor in combination with rituximab in patients with relapsed chronic lymphocytic leukemia. Haematologica- Hematol J. 2010;95:321–2.

    Google Scholar 

  10. Pepper C, Buggins AG, Jones CH, Walsby EJ, Forconi F, Pratt G, et al. Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kδ inhibition. Leukemia. 2015;29:744–7.

  11. Barretina J, Juncà J, Llano A, Gutiérrez A, Flores A, Blanco J, et al. CXCR4 and SDF-1 expression in B-cell chronic lymphocytic leukemia and stage of the disease. Ann Hematol. 2003;82:500–5.

    Article  CAS  PubMed  Google Scholar 

  12. Kriston C, Plander M, Márk Á, Sebestyén A, Bugyik E, Matolcsy A, et al. In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment. Ann Hematol. 2018;97:2145–52.

    Article  CAS  PubMed  Google Scholar 

  13. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745–60.

    Article  CAS  PubMed  Google Scholar 

  14. Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018;34:i884–i90.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    Article  CAS  PubMed  Google Scholar 

  17. Roberts A, Trapnell C, Donaghey J, Rinn JL, Pachter L. Improving RNA-Seq expression estimates by correcting for fragment bias. Genome Biol. 2011;12:R22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ganghammer S, Gutjahr J, Hutterer E, Krenn PW, Pucher S, Zelle-Rieser C, et al. Combined CXCR3/CXCR4 measurements are of high prognostic value in chronic lymphocytic leukemia due to negative co-operativity of the receptors. Haematologica. 2016;101:e99–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Majid A, Lin TT, Best G, Fishlock K, Hewamana S, Pratt G, et al. CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL. Leuk Res. 2011;35:750–6.

    Article  CAS  PubMed  Google Scholar 

  21. Ishibe N, Albitar M, Jilani IB, Goldin LR, Marti GE, Caporaso NE. CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia, but CD38 expression is not. Blood. 2002;100:1100–1.

    Article  CAS  PubMed  Google Scholar 

  22. Ahn IE, Tian X, Ipe D, Cheng M, Albitar M, Tsao LC, et al. Prediction of outcome in patients with chronic lymphocytic leukemia treated with Ibrutinib: Development and validation of a four-factor prognostic model. J Clin Oncol. 2020;39:576–85.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54.

    Article  CAS  PubMed  Google Scholar 

  24. Guièze R, Wu CJ. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood. 2015;126:445–53.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018;131:2283–96.

    Article  CAS  PubMed  Google Scholar 

  26. Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519–24.

    Article  CAS  PubMed  Google Scholar 

  28. Kulis M, Heath S, Bibikova M, Queirós AC, Navarro A, Clot G, et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat Genet. 2012;44:1236–42.

    Article  CAS  PubMed  Google Scholar 

  29. Beekman R, Chapaprieta V, Russiñol N, Vilarrasa-Blasi R, Verdaguer-Dot N, Martens JHA, et al. The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia. Nat Med. 2018;24:868–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–34.

    Article  CAS  PubMed  Google Scholar 

  31. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198–206.

    Article  CAS  PubMed  Google Scholar 

  32. Bartholdy BA, Wang X, Yan XJ, Pascual M, Fan M, Barrientos J, et al. CLL intraclonal fractions exhibit established and recently acquired patterns of DNA methylation. Blood Adv. 2020;4:893–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gattei V, Bulian P, Del Principe MI, Zucchetto A, Maurillo L, Buccisano F, et al. Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood. 2008;111:865–73.

    Article  CAS  PubMed  Google Scholar 

  34. Zucchetto A, Benedetti D, Tripodo C, Bomben R, Dal Bo M, Marconi D, et al. CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. Cancer Res. 2009;69:4001–9.

    Article  CAS  PubMed  Google Scholar 

  35. Alsadhan A, Chen J, Gaglione EM, Underbayev C, Tuma PL, Tian X, et al. CD49d Expression identifies a biologically distinct subtype of chronic lymphocytic leukemia with inferior progression-free survival on BTK inhibitor therapy. Clin Cancer Res. 2023;29:3612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zucchetto A, Caldana C, Benedetti D, Tissino E, Rossi FM, Hutterer E, et al. CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism. Blood. 2013;122:3317–21.

    Article  CAS  PubMed  Google Scholar 

  37. Benedetti D, Tissino E, Pozzo F, Bittolo T, Caldana C, Perini C, et al. NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways. Leukemia. 2018;32:654–62.

    Article  CAS  PubMed  Google Scholar 

  38. Tissino E, Pozzo F, Benedetti D, Caldana C, Bittolo T, Rossi FM, et al. CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression. Blood. 2020;135:1244–54.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Vaisitti T, Aydin S, Rossi D, Cottino F, Bergui L, D’Arena G, et al. CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells. Leukemia. 2010;24:958–69.

    Article  CAS  PubMed  Google Scholar 

  40. Möhle R, Failenschmid C, Bautz F, Kanz L. Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1). Leukemia. 1999;13:1954–9.

    Article  PubMed  Google Scholar 

  41. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–7.

    Article  CAS  PubMed  Google Scholar 

  42. Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N, et al. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood. 2005;106:1824–30.

    Article  CAS  PubMed  Google Scholar 

  43. Chen SS, Chang BY, Chang S, Tong T, Ham S, Sherry B, et al. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia. 2016;30:833–43.

    Article  CAS  PubMed  Google Scholar 

  44. Lewis R, Maurer HC, Singh N, Gonzalez-Menendez I, Wirth M, Schick M, et al. CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness. Leukemia. 2021;35:2895–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kluckova K, Clear AJ, D’Avola A, Rassenti LZ, Kipps TJ, Gribben JG, et al. B-cell receptor signaling induced metabolic alterations in chronic lymphocytic leukemia can be partially bypassed by TP53 abnormalities. Hemasphere. 2022;6:e722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Calissano C, Damle RN, Marsilio S, Yan X-J, Yancopoulos S, Hayes G, et al. Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born/divided and older/quiescent cells. Mol Med. 2011;17:1374–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Thavayogarajah T, Sinitski D, El Bounkari O, Torres-Garcia L, Lewinsky H, Harjung A, et al. CXCR4 and CD74 together enhance cell survival in response to macrophage migration-inhibitory factor in chronic lymphocytic leukemia. Exp Hematol. 2022;115:30–43.

    Article  CAS  PubMed  Google Scholar 

  48. Andritsos LA, Byrd JC, Cheverton P, Wu J, Sivina M, Kipps TJ, et al. A multicenter phase 1 study of plerixafor and rituximab in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2019;60:3461–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was kindly supported by the Science and Technology Project of Sichuan Province of China (Grant No. 2022YFS0213, 2023NSFSC1483, 2023NSFSC1484 and 2023YFS0187), the 1 3 5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University (Grant No. 2023HXFH034).

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China

    Xinran Xue, Zhihao Wen, Xin Zhang, Ying Yang, Yifei Li, Ruoxi Liao, Qin Zheng, Yang Fu, Yu Liu & Hongyan Liao

Authors
  1. Xinran Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhihao Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yifei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ruoxi Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qin Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yang Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hongyan Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xinran Xue and Hongyan Liao designed the study. Xinran Xue wrote the main manuscript text. Zhihao Wen, Xin Zhang, Ying Yang, Yifei Li and Qin Zheng performed immunophenotyping, acquired the data and analysed and/or interpreted the data. Xinran Xue, Ruoxi Liao, Qin Zheng, Yang Fu and Yu Liu revised the manuscript. Yu Liu, Qin Zheng, Yang Fu, and Hongyan Liao acquired the fundings. Hongyan Liao supervised the study and edited the original draft. All authors reviewed the manuscript.

Corresponding author

Correspondence to Hongyan Liao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics

All included subjects signed an informed consent form. The study protocol was in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of West China Hospital of Sichuan University.

Additional information

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

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

Xue, X., Wen, Z., Zhang, X. et al. CXCR4 overexpression in chronic lymphocytic leukemia associates with poorer prognosis: A prospective, single-center, observational study. Genes Immun 25, 117–123 (2024). https://doi.org/10.1038/s41435-024-00258-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-024-00258-7

Search

Advanced search

Quick links