Advertisement

Comparative Clinical Pathology

, Volume 28, Issue 1, pp 33–40 | Cite as

Prognostic relevance of CD69 expression in B cell chronic lymphocytic leukemia

  • Salah ArefEmail author
  • Nadia El Menshawy
  • Mohamed Sabry El-Ghonemy
  • Ghada El-Said
  • Mohamed Ali El-Baiomy
Original Article
  • 45 Downloads

Abstract

This study aimed to determine the prognostic impact of CD69 expression in B cell chronic lymphocytic leukemia (CLL). The study included 153 B cell chronic lymphocytic leukemia (B-CLL) recruited to Mansoura Oncology Center. Cellular CD69 expression was determined by multicolor flow cytometry in parallel with PCR amplification and sequencing analysis to mutational status of immunoglobulin variable heavy chain (IgVH). The number of CLL patients positively expressed CD69 was 47 out of 153 (30.7%). There is significant association between CD69-positive expression and unmutated IgVH and between CD69 negative expressions with mutated IgVH gene (P < 0.007). The patients positively expressed CD69 were younger in age and had higher leukocyte count, advanced RIA stages III and IV, and high β2 microglobulin as compared to negative ones. CLL patients group positively expressed CD69 had short overall survival and progression disease-free survival (PDFS) as compared to negative ones. Cox proportional hazard regression model showed that positive CD69 expression is an independent prognostic biomarker for progression-free survival (HR for CD69 vs IgVH was 1.7 vs 1.6, p = 0.04 vs 0.02) and OS (HR 1.8 vs 1.9, p = 0.03 vs 0.01). In conclusion, positive CD69 expression could predict adverse outcome; it could be included in scoring system of CLL as simple, easy applicable to stratify early progressive patients and enabling timely therapeutic decisions to improve outcome. Also, it could be a target for therapy for B cell CLL.

Keywords

CLL CD69 Prognosis 

Notes

Compliance with ethical standards

This study did not include animals.

Informed consent was taken from all subjects participate in this study.

Conflict of interest

The authors declare that there is no conflict of interest.

References

  1. Bomben R, Dal Bo M, Zucchetto A, Zaina E, Nanni P, Sonego P, Del Poeta G, Degan M, Gattei V (2005) Mutational status of IgV(H) genes in B-cell chronic lymphocytic leukemia and prognosis: percent mutations or antigen-driven selection? Leukemia 19(8):1490–1492CrossRefGoogle Scholar
  2. Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T, Rassenti L, Weiss A, Kipps T (2005) ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 105(5):2036–2041CrossRefGoogle Scholar
  3. D’Arena G, Musto P, Nunziata G, Cascavilla N, Savino L, Pistolese G (2001) CD69 expression in B-cell chronic lymphocytic leukemia: a new prognostic marker? Haematologica 86(9):995–996Google Scholar
  4. Damle RN, Ghiotto F, Valetto A, Albesiano E, Fais F, Yan XJ et al (2002) B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen experienced B lymphocytes. Blood 99(11):4087–4935CrossRefGoogle Scholar
  5. Damle RN, Temburni S, Calissano C, Yancopoulos S, Banapour T, Sison C, Sison C, Allen SL, Rai KR, Chiorazzi N (2007) CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells. Blood 110(9):3352–3359CrossRefGoogle Scholar
  6. Deaglio S, Capobianco A, Bergui L, Durig J, Morabito F, Duhrsen U, Malavasi F (2003) CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells. Blood 102:2146–2155CrossRefGoogle Scholar
  7. Deaglio S, Vaisitti T, Aydin S, Ferrero E, Malavasi F (2006) In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia. Blood 108:1135–1144CrossRefGoogle Scholar
  8. Deane M, Norton JD (1990) Detection of immunoglobulin gene reaarangement in B-lymphoid malignancies by polymerase chain reaction amplification. Br J Haematol 74:251–256CrossRefGoogle Scholar
  9. Deane M, Norton JD (1991) Immunoglobulin gene ‘fingerprinting’: an approach to analysis of B lymphoid clonality in lymphoproliferative disorders. Br J Haematol 77:274–281CrossRefGoogle Scholar
  10. Del Poeta G, Del Principe M, Zucchetto A, Luciano F, Buccisano F, Rossi F, Bruno A, Biagi A, Bulian P, Maurillo L, Neri B, Bomben R, Simotti C, Coletta A, Dal Bo M, Fabritiis P, Venditti A, Gattei V, Amadori S (2012) CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study. Haematologica 97(2):279–287CrossRefGoogle Scholar
  11. El-hadi E, El-Sakhawy Y, Osman A (2015) Evaluation of CD69 expression as a prognosticator in chronic lymphocytic leukemia. Egypt J Haematol 40:113–120CrossRefGoogle Scholar
  12. Esplugues E, Vega-Ramos J, Cartoixa D, Vazquez BN, Salaet I, Engel P, Lauzurica P (2005) Induction of tumor NK-cell immunity by anti-CD-69 antibody therapy. Blood 105:4399–4406CrossRefGoogle Scholar
  13. Gattei V, Principe MI, Zucchetto A, Maurillo L, Buccisano F, Bomben R, Dal-Bo M, Luciano F, Rossi FM, Degan M, Amadori S, Del Poeta G (2008) Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood 111(2):865–873CrossRefGoogle Scholar
  14. Grund S, Olsson B, Jernas M, Jacobsson S, Wadenvik H (2010) CD69 is a good surrogate marker for IgVH gene mutation status in Swedish chronic lymphocytic leukemia (CLL) patients. Acta Haematol Pol 41:57–64Google Scholar
  15. Guarini A, Chiaretti S, Tavolaro S, Maggio R, Peragine N, Citarella F, Ricciardi M, Santangelo S, Marinelli M, De Propris M, Messina M, Mauro F, Del Giudice I, Foà R (2008) BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgVH unmutated chronic lymphocytic leukemia (CLL) cells. Blood 112(3):782–792CrossRefGoogle Scholar
  16. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94(6):1848–1854Google Scholar
  17. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK, Oscier DG (2002) CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 99:1023–1029CrossRefGoogle Scholar
  18. Hamilton E, Pearce L, Morgan L, Robinson S, Ware V, Brennan P, Thomas NS, Yallop D, Devereux S, Fegan C, Buggins AG, Pepper C (2012) Mimicking the tumour microenvironment: three different co-culture systems induce a similar phenotype but distinct proliferative signals in primary chronic lymphocytic leukaemia cells. Br J Haematol 158:589–599CrossRefGoogle Scholar
  19. Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, Herishanu Y, Pérez-Galán P, Liu D, Biancotto A, Pittaluga S, Vire B, Gibellini F, Njuguna N, Lee E, Stennett L, Raghavachari N, Liu P, McCoy JP, Raffeld M, Stetler-Stevenson M, Yuan C, Sherry R, Arthur DC, Maric I, White T, Marti GE, Munson P, Wilson WH, Wiestner A (2011) The lymph node microenvironment promotes B-cell receptor signaling, NF-{kappa} B activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117(2):563–574CrossRefGoogle Scholar
  20. Huang PY, Best OG, Belov L, Mulligan SP, Christopherson RI (2012) Surface profiles for subclassification of chronic lymphocytic leukemia. Leuk Lymphoma 53:1046–1056CrossRefGoogle Scholar
  21. Ibrahim S, Keating M, Do KA, O'Brien S, Huh YO, Jilani I, Lerner S, Kantarjian HM, Albitar M (2001) CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 98:181–186CrossRefGoogle Scholar
  22. Marzio R, Manuel J, Betz-Corradin S (1999) CD69and regulation of the immune function. Immunopharmacol Immunotoxicol 21(3):365–382CrossRefGoogle Scholar
  23. Montraveta A, Lee-Vergés E, Roldán J, Jiménez L, Cabezas S, Clot G, Pinyol M, Xargay-Torrent S, Rosich L, Arimany-Nardí C, Aymerich M, Villamor N, López-Guillermo A, Pérez-Galán P, Roué G, Pastor-Anglada M, Campo E, López-Guerra M, Colomer D (2016) CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia. Oncotarget 7(5):5507–5520CrossRefGoogle Scholar
  24. Moreno C, Montserrat E (2008) New prognostic markers in chronic lymphocytic leukemia. Blood Rev 22:211–219CrossRefGoogle Scholar
  25. Murata K, Inami M, Hasegawa A, Kubo S, Kimura M, Yamashita M, Hosokawa H, Nagao T, Suzuki K, Hashimoto K, Shinkai H, Koseki H, Taniguchi M, Ziegler S, Nakayama T (2003) CD69-null mice protected from arthritis induced with anti-type II collagen antibodies. Int Immunol 15:987–992CrossRefGoogle Scholar
  26. Navarro GA, Bjorklund TA and Chekeny M (2015). Therapeutic potential and challenges of natural killer cells in treatment of solid tumors. Front Immunol.  https://doi.org/10.3389/fimmu.00202
  27. Palma M, Gentilcore G, Heimersson K, Mozaffari F, Näsman-Glaser B, Young E, Rosenquist R, Hansson L, Österborg A, Mellstedt H (2016) T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. Haematologica 102(3):562–572CrossRefGoogle Scholar
  28. Patten PE, Buggins AG, Richards J, Wotherspoon A, Salisbury J, Mufti GJ, Hamblin TJ, Devereux S (2008) CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood 111:5173–5181CrossRefGoogle Scholar
  29. Plander M, Seegers S, Ugocsai P, Diermeier-Daucher S, Ivanyi J, Schmitz G, Hofstadter F, Schwarz S, Orso E, Knuchel R, Brockhoff G (2009) Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudo follicles. Leukemia 23:2118–2128CrossRefGoogle Scholar
  30. Radulovic K, Rossini V, Manta C, Holzmann K, Kestler H, Niess J (2013) The early activation marker CD69 regulates the expression of chemokines and CD4 T cell accumulation in intestine. PLoS One 8(6):e65413CrossRefGoogle Scholar
  31. Rosenquist R, Cortese D, Bhoi S, Mansouri L, Gunnarsson R (2013) Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lymphoma 54:2351–2364CrossRefGoogle Scholar
  32. Sancho D, Gomez M, Sanchez-Madrid F (2005) CD69 is an immunoregulatory molecule induced following activation. Trends Immunol 26(3):136–1340CrossRefGoogle Scholar
  33. Sargent R, Craig F, Swerdlow S (2009) Comparison of Bcl-2, CD 38 and ZAP-70 expression in chronic lymphocytic leukemia. Int J Clin Pathol 2:574–582Google Scholar
  34. Smilevska T, Stamatopoulos K, Samara M, Belessi C, Tsompanakou A, Paterakis G, Stavroyianni N, Athanasiadou L, Chiotoglou L, Hadzidimitriou A, Athanasiadou A, Douka V, Saloum R, Laoutaris N, Anagnostopoulos A, Athanasios Fassas A, Nikolaos Stathakis N, Kollia P (2006) Transferrin receptor-1 and 2 expressions in chronic lymphocytic leukemia. Leuk Res 30(2):183–189CrossRefGoogle Scholar
  35. Zucchetto A, Bomben R, Dal Bo M, Sonego P, Nanni P, Rupolo M, Bulian P, Dal Maso L, Del Poeta G, Del Principe MI, Degan M, Gattei V (2006) A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia. J Cell Physiol 207(2):354–363CrossRefGoogle Scholar
  36. Zwiebel JA, Cheson BD (1998) Chronic lymphocytic leukemia: staging and prognostic factors. Semin Oncol 25(1):42–59Google Scholar

Copyright information

© Springer-Verlag London Ltd., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Hematology Unit, Clinical pathology DepartmentMansoura University Oncology Center, Mansoura Faculty of MedicineMansouraEgypt
  2. 2.Internal Medicine DepartmentMansoura University Oncology Center, Mansoura Faculty of MedicineMansouraEgypt
  3. 3.Medical Oncology unitMansoura University Oncology Center, Mansoura Faculty of MedicineMansouraEgypt

Personalised recommendations