Abstract
Bcl-2, the gene over-expressed in follicular lymphomas (FL), is able to block chemotherapy-induced apoptosis. Consequently, we wondered whether bcl-2/IgH expression variations during treatment of FL could predict the outcome of patients with t(14;18)-bearing FL. For this purpose, we used a reverse transcription polymerase chain reaction (RT-PCR) assay to analyse 180 serial peripheral blood samples (PBS) during 34 treatment phases in 25 patients with t(14;18)-bearing FL. In all patients but two, bcl-2/IgH gene expression was demonstrated in pre-treatment samples. During 16 out of the 34 treatment phases (47%), bcl-2/IgH expression became negative: all but one were responders to chemotherapy. This conversion was transient in six cases. In 18 treatment phases, bcl2/IgH expression remained detectable: eight were clinically considered as treatment failures, while eight others achieved PR and two achieved CR. We observed a significant correlation between treatment response and RNA PCR results (P = 0.002). Three-year overall survival of patients with stable bcl2/IgH-negative conversion was 100% compared to 54% for the remaining patients (P = 0.069); 3-year freedom from progression was respectively 87.5% and 13% (P = 0.005). These results indicate a correlation between bcl-2/IgH expression variations and both clinical response and outcome. Whether this might predict disease outcome early remains to be confirmed.
Article PDF
Similar content being viewed by others
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Alnemri, ES, Fernandes, TF, Haldar, S, Croce, CM & Litwack, G (1992) Involvement of BCL-2 in glucocorticoid-induced apoptosis of human pre-B-leukemias. Cancer Res 52: 491–495.
Aster, JC, Kobayashi, Y, Shiota, M, Mori, S & Sklar, J (1992) Detection of the t(14;18) at similar frequencies in hyperplastic lymphoid tissues from American and Japanese patients. Am J Pathol 141: 291–299.
Bell, DA, Liu, Y & Cortopassi, GA (1995) Occurrence of bcl-2 oncogene translocation with increased frequency in the peripheral blood of heavy smokers. J Natl Cancer Inst 87: 223–224.
Bierman, PJ, Vose, JM, Anderson, JR, Bishop, MR, Kessinger, A & Armitage, JO (1997) High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin’s lymphoma. J Clin Oncol 15: 445–450.
Bonadonna, G, Viviani, S, Valagussa, P, Bonfante, V & Santoro, A (1985) Third-line salvage chemotherapy in Hodgkin’s disease. Semin Oncol 12, (suppl 2) 23–25.
Chauvergne, J, Durand, M, Hoerni, B, Hoerni-Simon, G, Brunet, R & Lagarde, C (1977) Induction chemotherapy of non-Hodgkin’s malignant lymphomas. Preliminary results of a controlled trial. Eur J Cancer 13: 399–400.
Cleary, ML, Smith, SD & Sklar, J (1986) Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47: 19–28.
Corbally, N, Grogan, L, Keane, MM, Devaney, DM, Dervan, PA & Carney, DN (1994) Bcl-2 rearrangement in Hodgkin’s disease and reactive lymph nodes. Am J Clin Pathol 101: 756–760.
Dolken, G, Illerhaus, G, Hirt, C & Mertelsmann, R (1996) BCL-2/J(H) rearrangements in circulating B cells of healthy blood donors and patients with non-malignant diseases. J Clin Oncol 14: 1333–1344.
Freedman, AS, Gribben, JG, Neuberg, D, Mauch, P, Soiffer, RJ, Anderson, KC, Pandite, L, Robertson, MJ, Kroon, M, Ritz, J & Nadler, LM (1996) High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 88: 2780–2786.
Fuscoe, JC, Setzer, RW, Collard, DD & Moore, MM (1996) Quantification of t(14;18) in the lymphocytes of healthy adult humans as a possible biomarker for environmental exposures to carcinogens. Carcinogenesis 17: 1013–1020.
Gribben, JG (1994) Attainment of molecular remission: a worthwhile goal?. J Clin Oncol 12: 1532–1534.
Gribben, JG, Freedman, AS, Neuberg, D, Roy, DC, Blake, KW, Woo, SD, Grossbard, ML, Rabinowe, SN, Coral, F, Freeman, GJ, Ritz, J & Nadler, LM (1991) Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 325: 1525–1533.
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 (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84: 1361–1392.
Hockenbery, D, Nunez, G, Milliman, C, Schreiber, RD & Korsmeyer, SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334–336.
Ji, WZ, Qu, GZ, Ye, P, Zhang, XY, Halabi, S & Ehrlich, M (1995) Frequent detection of bcl-2/J(H) translocations in human blood and organ samples by a quantitative polymerase chain reaction assay. Cancer Res 55: 2876–2882.
Kamesaki, S, Kamesaki, H, Jorgensen, TJ, Tanizawa, A, Pommier, Y & Cossman, J (1993) Bcl-2 protein inhibits etoposide-induced apoptosis through its effects on events subsequent to topoisomerase II-induced DNA strand breaks and their repair. Cancer Res 53: 4251–4256.
Keith, FJ, Bradbury, DA, Zhu, YM & Russell, NH (1995) Inhibition of bcl-2 with antisense oligonucleotides induces apoptosis and increases the sensitivity of AML blasts to Ara-C. Leukemia 9: 131–138.
Kitada, S, Takayama, S, De Riel, K, Tanaka, S & Reed, JC (1994) Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression. Antisense Res Dev 4: 71–79.
Kwok, S & Higuchi, R (1989) Avoiding false positive with PCR. Nature 339: 237–238.
Lennert, K & Feller, AC (1992). Histopathology of non-Hodgkin’s lymphomas. Springer-Verlag: Berlin
Limpens, J, de Jong, D, van Krieken, JH, Price, CG, Young, BD, van Ommen, GJ & Kluin, PM (1991) Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia. Oncogene 6: 2271–2276.
Limpens, J, Stad, R, Vos, C, de Vlaam, C, de Jong, D, van Ommen, GJ, Schuuring, E & Kluin, PM (1995) Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 85: 2528–2536.
Linette, GP, Li, Y, Roth, K & Korsmeyer, SJ (1996) Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation – inaugural paper. Proc Natl Acad Sci USA 93: 9545–9552.
Liu, Y, Hernandez, AM, Shibata, D & Cortopassi, GA (1994) BCL2 translocation frequency rises with age in humans. Proc Natl Acad Sci USA 91: 8910–8914.
Lotem, J & Sachs, L (1993) Regulation by bcl-2, c-myc, and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation-competent and -defective myeloid leukemic cells. Cell Growth Differ 4: 41–47.
McLaughlin, P, Hagemeister, FB, Romaguera, JE, Sarris, AH, Pate, O, Younes, A, Swan, F, Keating, M & Cabanillas, F (1996) Fludarabine, mitoxantrone, and dexamethasone: An effective new regimen for indolent lymphoma. J Clin Oncol 14: 1262–1268.
Mazel, S, Burtrum, D & Petrie, HT (1996) Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death. J Exp Med 183: 2219–2226.
Miller, AB, Hoogstraten, B, Staquet, M & Winkler, A (1981) Reporting results of cancer treatment. Cancer 47: 207–214.
Miyashita, T & Reed, JC (1992) Bcl-2 gene transfer increases relative resistance of S49.1 and WEH17.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 52: 5407–5411.
Miyashita, T & Reed, JC (1993) Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81: 151–157.
O’Reilly, LA, Huang, DCS & Strasser, A (1996) The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J 15: 6979–6990.
Ohshima, K, Kikuchi, M, Kobari, S, Masuda, Y, Eguchi, F & Kimura, N (1993) Amplified bcl-2/JH rearrangements in reactive lymphadenopathy. Virchows Arch B Cell Pathol Incl Mol Pathol 63: 197–198.
Price, CG, Tuszynski, A, Watt, SM, Murdoch, SJ, Lister, TA & Young, BD (1991) Detection of additional JH/BCL2 translocations in follicular lymphoma. Leukemia 5: 548–554.
Ravetch, JV, Siebenlist, U, Korsmeyer, S, Waldmann, T & Leder, P (1981) Structure of the human immunoglobulin locus: characterization of embryonic and rearranged J and D genes. Cell 27: 583–591.
Reed, JC, Kitada, S, Takayama, S & Miyashita, T (1994) Regulation of chemoresistance by the bcl-2 oncoprotein in non-Hodgkin’s lymphoma and lymphocytic leukemia cell lines. Ann Oncol 5, (suppl 1) S61–S65.
Richaud, PM, Soubeyran, P, Eghbali, H, Chacon, B, Marit, G, Broustet, A & Hœrni, B (1998) Place of low-dose total body irradiation in the treatment of localized follicular non-Hodgkin’s lymphoma: Results of a pilot study. Int J Radiat Oncol Biol Phys 40: 387–390.
Rohatiner, AZ, Johnson, PW, Price, CG, Arnott, SJ, Amess, JA, Norton, AJ, Dorey, E, Adams, K, Whelan, JS, Matthews, J, MacCallum, PK, Oza, AM & Lister, TA (1994) Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol 12: 1177–1184.
Sambrook, J, Fritsch, EF & Maniatis, T (1989). Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor
Solal-Celigny, P, Lepage, E, Brousse, N, Reyes, F, Haioun, C, Leporrier, M, Peuchmaur, M, Bosly, A, Parlier, Y, Brice, P, Coiffier, B & Gisselbrecht, C (1993) Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d’Etude des Lymphomes de l’Adulte. N Engl J Med 329: 1608–1614.
Soubeyran, P, Eghbali, H, Bonichon, F, Coindre, JM, Richaud, P & Hœrni, B (1988) Localized follicular lymphomas: prognosis and survival of stages I and II in a retrospective series of 103 patients. Radiother Oncol 13: 91–98.
Soubeyran, P, Eghbali, H, Bonichon, F, Trojani, M, Richaud, P & Hœrni, B (1991) Low-grade follicular lymphomas: analysis of prognosis in a series of 281 patients. Eur J Cancer 27: 1606–1613.
Soubeyran, P, Cabanillas, F & Lee, MS (1993) Analysis of the expression of the hybrid gene bcl-2/IgH in follicular lymphomas. Blood 81: 122–127.
Tsujimoto, Y & Croce, CM (1986) Analysis of the structure, transcripts, and protein products ob bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci USA 83: 5214–5218.
Vairo, G, Innes, KM & Adams, JM (1996) Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene 13: 1511–1519.
Weiss, LM, Warnke, RA, Sklar, J & Cleary, ML (1987) Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 317: 1185–1189.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Soubeyran, P., Hostein, I., Debled, M. et al. Evolution of BCL-2/IgH hybrid gene RNA expression during treatment of T(14;18)-bearing follicular lymphomas. Br J Cancer 81, 860–869 (1999). https://doi.org/10.1038/sj.bjc.6690777
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690777
- Springer Nature Limited