Abstract
Mantle cell lymphoma (MCL) is a tumor of intermediate-size, IgM+, IgD+ B cells derived from the mantle zone of the germinal center. Little is known about its specific immunologic features or responsiveness to T cell-derived signals. In this work, we evaluated the proliferation and cell cycle properties of freshly isolated MCL cells after CD40 ligation, in the absence and presence of interleukin 4 (IL-4). In each MCL case examined, there was a marked growth-enhancing effect of these two stimuli characterized by improved viability, augmented expression of Ki-67, and induction of the proliferating cell nuclear antigen (PCNA). Cyclin D1 was expressed throughout the cell cycle in MCL cells induced to enter S phase. From these investigations, we conclude that the biology of MCL B lymphocytes is affected by CD154 (CD40 ligand) and IL-4, two signals usually provided by CD4+ T cells. The capacity to manipulate the activation and cell cycle state of MCL cells by these specific immunological stimuli may be exploited to confer susceptibility to chemotherapy agents and develop novel therapies in this disease.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hummel M, Tamaru J, Kalvelage B, Stein H . Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle Blood 1994 84: 403–407
Weisenburger DD, Armitage JO . Mantle cell lymphoma – an entity comes of age Blood 1996 87: 4483–4494
Project N-HsLC . A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project Blood 1997 89: 3909–3918
Banks PM, Chan J, Cleary ML, Delsol G, De Wolf-Peeters C, Gatter K, Grogan TM, Harris NL, Isaacson PG, Jaffe ES et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data Am J Surg Pathol 1992 16: 637–640
Fisher RI, Dahlberg S, Nathwani BN, Banks PM, Miller TP, Grogan TM . A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study Blood 1995 85: 1075–1082
Jaffe ES, Bookman MA, Longo DL . Lymphocytic lymphoma of intermediate differentiation – mantle zone lymphoma: a distinct subtype of B-cell lymphoma Hum Pathol 1987 18: 877–880
De Oliveira MS, Jaffe ES, Catovsky D . Leukaemic phase of mantle zone (intermediate) lymphoma: its characterisation in 11 cases J Clin Pathol 1989 42: 962–972
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink HK, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA . A revised European–American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group Blood 1994 84: 1361–1392
Sherr CJ . G1 phase progression: cycling on cue Cell 1994 79: 551–555
de Boer CJ, Schuuring E, Dreef E, Peters G, Bartek J, Kluin PM, van Krieken JH . Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma Blood 1995 86: 2715–2723
Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S . The CD40 antigen and its ligand Annu Rev Immunol 1994 12: 881–922
Lederman S, Yellin MJ, Krichevsky A, Belko J, Lee JJ, Chess L . Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help) J Exp Med 1992 175: 1091–1101
Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A . A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells Proc Natl Acad Sci USA 1992 89: 6550–6554
Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC . Mechanism of antigen-driven selection in germinal centres Nature 1989 342: 929–931
Banchereau J, de Paoli P, Valle A, Garcia E, Rousset F . Long-term human B cell lines dependent on interleukin-4 and antibody to CD40 Science 1991 251: 70–72
Ledbetter JA, Shu G, Gallagher M, Clark EA . Augmentation of normal and malignant B cell proliferation by monoclonal antibody to the B cell-specific antigen BP50 (CDW40) J Immunol 1987 138: 788–794
Bishop J, Schattner EJ, Friedman SM . CD40 ligation impedes lymphoblastoid B cell proliferation and S-phase entry Leukemia Res 1998 22: 319–327
Funakoshi S, Longo DL, Beckwith M, Conley DK, Tsarfaty G, Tsarfaty I, Armitage RJ, Fanslow WC, Spriggs MK, Murphy WJ . Inhibition of human B-cell lymphoma growth by CD40 stimulation Blood 1994 83: 2787–2794
Crawford DH, Catovsky D . In vitro activation of leukaemic B cells by interleukin-4 and antibodies to CD40 Immunology 1993 80: 40–44
Cerutti A, Zan H, Schaffer A, Bergsagel L, Harindranath N, Max EE, Casali P . CD40 ligand and appropriate cytokines induce switching to IgG, IgA, and IgE and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM+IgD+ B cell line J Immunol 1998 160: 2145–2157
Defrance T, Fluckiger AC, Rossi JF, Magaud JP, Sotto JJ, Banchereau J . Antiproliferative effects of interleukin-4 on freshly isolated non-Hodgkin malignant B-lymphoma cells Blood 1992 79: 990–996
Schwarz MA, Tardelli L, Macosko HD, Sullivan LM, Narula SK, Fine JS . Interleukin 4 retards dissemination of a human B-cell lymphoma in severe combined immunodeficient mice Cancer Res 1995 55: 3692–3696
Galibert L, Durand I, Banchereau J, Rousset F . CD40-activated surface IgD-positive lymphocytes constitute the long term IL-4-dependent proliferating B cell pool J Immunol 1994 152: 22–29
Yellin MJ, Lee JJ, Chess L, Lederman S . A human CD4− T cell leukemia subclone with contact-dependent helper function J Immunol 1991 147: 3389–3395
Zhi-Jun Y, Sriranganathan N, Vaught T, Arastu SK, Ahmed SA . A dye-based lymphocyte proliferation assay that permits multiple immunological analyses: mRNA, cytogenetic, apoptosis, and immunophenotyping studies J Immunol Meth 1997 210: 25–39
de Fries R, Mitsuhashi M . Quantification of mitogen induced human lymphocyte proliferation: comparison of alamarBlue assay to 3H-thymidine incorporation assay J Clin Lab Anal 1995 9: 89–95
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H . Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67 J Immunol 1984 133: 1710–1715
Prelich G, Kostura M, Marshak DR, Mathews MB, Stillman B . The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro Nature 1987 326: 471–475
Levin DS, Bai W, Yao N, M OD, Tomkinson AE . An interaction between DNA ligase I and proliferating cell nuclear antigen: implications for Okazaki fragment synthesis and joining Proc Natl Acad Sci USA 1997 94: 12863–12868
Kamel OW, Warnke RA, Banks PM . Localization of proliferating cell nuclear antigen (PCNA/Cyclin) in workshop cases of Hodgkin's disease and non-Hodgkin's lymphoma Semin Diagn Pathol 1992 9: 311–314
Hunter T, Pines J . Cyclins and cancer. II: cyclin D and CDK inhibitors come of age Cell 1994 79: 573–582
Heath AW, Chang R, Harada N, Santos-Argumedo L, Gordon J, Hannum C, Campbell D, Shanafelt AB, Clark EA, Torres R et al. Antibodies to murine CD40 stimulate normal B lymphocytes but inhibit proliferation of B lymphoma cells Cell Immunol 1993 152: 468–480
Schattner EJ, Elkon KB, Yoo DH, Tumang J, Krammer PH, Crow MK, Friedman SM . CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway J Exp Med 1995 182: 1557–1565
Schattner EJ, Mascarenhas J, Bishop J, Yoo DH, Chadburn A, Crow MK, Friedman SM . CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells Blood 1996 88: 1375–1382
Romano MF, Lamberti A, Tassone P, Alfinito F, Costantini S, Chiurazzi F, Defrance T, Bonelli P, Tuccillo F, Turco MC, Venuta S . Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells Blood 1998 92: 990–995
Schattner EJ . CD40 ligand in CLL pathogenesis and therapy Leuk Lymphoma (in press)
Bishop GA, Ramirez LM, Koretzky GA . Growth inhibition of a B cell clone mediated by ligation of IL-4 receptors or membrane IgM J Immunol 1993 150: 2565–2574
Akashi K . The role of interleukin-4 in the negative regulation of leukemia cell growth Leuk Lymphoma 1993 9: 205–209
Fluckiger AC, Rossi JF, Bussel A, Bryon P, Banchereau J, Defrance T . Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors Blood 1992 80: 3173–3181
Dancescu M, Rubio-Trujillo M, Biron G, Bron D, Delespesse G, Sarfati M . Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression J Exp Med 1992 176: 1319–1326
Tallman MS, Hakimian D . Purine nucleoside analogs: emerging roles in indolent lymphoproliferative disorders Blood 1995 86: 2463–2474
Acknowledgements
This work was supported with funds from The Dorothy Rodbell Cohen Foundation for Sarcoma Research and National Institutes of Health grant CA71589.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Castillo, R., Mascarenhas, J., Telford, W. et al. Proliferative response of mantle cell lymphoma cells stimulated by CD40 ligation and IL-4. Leukemia 14, 292–298 (2000). https://doi.org/10.1038/sj.leu.2401664
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2401664
Keywords
This article is cited by
-
Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib
Scientific Reports (2023)
-
Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma
BMC Cancer (2021)
-
CD40L mediated alternative NFκB-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma
Cell Death & Disease (2018)
-
Multifunctional CD40L: pro- and anti-neoplastic activity
Tumor Biology (2014)
-
Priming effect of aspirin for tumor cells to augment cytotoxic action of cisplatin against tumor cells: implication of altered constitution of tumor microenvironment, expression of cell cycle, apoptosis, and survival regulatory molecules
Molecular and Cellular Biochemistry (2012)