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Lymphoma Remission and Relapse in a Low-Grade CD70 Ligation

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Lymphoma Remission and Relapse in a Low-Grade CD70 Ligation Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021 is online at: average * The Journal of Immunology , 14 of which you can access for free at: 2005; 175:6940-6947; ; from submission to initial decision 4 weeks from acceptance to publication J Immunol doi: 10.4049/jimmunol.175.10.6940 http://www.jimmunol.org/content/175/10/6940 Proliferation Response of Leukemic Cells to CD70 Ligation Oscillates with Recurrent Remission and Relapse in a Low-Grade Lymphoma Yael Kaufmann, Ninette Amariglio, Esther Rosenthal, Yasmine Jacob Hirsch, Amira Many and Gideon Rechavi cites 34 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2005/11/03/175.10.6940.DC1 This article http://www.jimmunol.org/content/175/10/6940.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* • Why • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 28, 2021. The Journal of Immunology Proliferation Response of Leukemic Cells to CD70 Ligation Oscillates with Recurrent Remission and Relapse in a Low-Grade Lymphoma1 Yael Kaufmann,2*‡ Ninette Amariglio,*† Esther Rosenthal,* Yasmine Jacob Hirsch,† Amira Many,* and Gideon Rechavi3*†‡ Interactions of the TNF-related cell surface ligand CD70 with its receptor CD27 provide a costimulatory signal in B and T cell activation. Functional CD70-CD27 interactions could contribute to lymphoma and leukemia progression. This possibility was studied using DNA microarrays on a unique case of low-grade lymphoma/leukemia characterized by recurrent cycles of acute leukemic phase alternating with spontaneous remission. Upon induction of the acute phase expression of CD70 and CD27 in the leukemic cells increased 38- and 25-fold, respectively. Coexpression of membrane CD70 and CD27 on the Downloaded from leukemic (CD5؉CD19؉) cells was maximal 2–3 days following initiation of the attack. Soluble CD27 in the patient’s serum was elevated during remission and further increased in the attack. Functional tests showed that neither anti-CD70 nor anti-CD27 Abs affect the rate of apoptosis. However, the anti-CD70 Ab specifically enhanced proliferation of the remission phase leukemic cells, whereas proliferation of the acute-phase counterparts that express higher level of membrane CD70 was unaffected. Hence, in this lymphoma/leukemia, membrane CD70 is presented on the leukemic cells in a responsive state during the remission and a nonresponsive state during the attack. Presumably, CD70 in its responsive state provides a http://www.jimmunol.org/ costimulatory receptor for initiating the next acute phase while its nonresponsive state enables the remission. The Journal of Immunology, 2005, 175: 6940–6947. nteractions between TNFR family members and their ligands tor ligand pair have mainly addressed the ability of CD27 to control lymphocyte death, survival, proliferation, and dif- regulate the immune response. CD27 signaling appears to play I ferentiation (1, 2). CD27 and its ligand CD70 are members a costimulatory role promoting T cell expansion and differen- of the TNFR family and TNF superfamily, respectively. Tightly tiation (7, 12–15), as well as enhancement of NK cell activity regulated expression of CD70 and CD27 on normal lympho- (16). CD70 has been generally envisaged as a passive element by guest on September 28, 2021 cytes ensures the transient availability of these costimulatory merely required for specific CD27 engagement. Yet, reverse signals. CD70 is induced transiently upon activation of B cells signaling of CD70 was reported. Thus, anti-CD70 mAbs were (3) and T cells (4). CD27 is absent from immature and mature observed to induce proliferation in a subset of B cell chronic B cells but is found on memory B cells (5, 6), T cells (7), and lymphocytic leukemia (CLL) (17) and stimulate NK and ␥␦ T NK cells (8). Differentiation to effector T cells is associated to cell-mediated redirected killing (18), suggesting that CD70 loss of CD27 (9). Cell surface CD27 can be proteolytically might be a signaling molecule. Recently Arens et al. (19) 4 cleaved to produce a 32-kDa soluble CD27 (sCD27) molecule, showed that CD70 has reverse signaling properties in murine B which can be detected in the serum and urine (10). Elevated cells, initiating a signaling cascade that regulates expansion and serum sCD27 levels are seen in a number of infectious and differentiation. In contrast to the tightly regulated expression of autoimmune disease states and are believed to be a marker of T CD70 on normal cells, constitutive expression of CD70 is found cell activation. Also, various types of B cell malignancies ex- on several human leukemias and lymphomas (17, 20, 21). The press the CD27 molecule and elevated serum levels of sCD27. finding that cross-linking of CD70 on malignant B cells aug- There appeared to be a correlation between tumor load and ments proliferation (17) raised the possibility that CD70 might sCD27 levels (11). Studies on the biological role of this recep- contribute to progression of these B cell malignancies. We have reported previously a case of CD5-positive B cell *Institute of Hematology and †Pediatric Hematology-Oncology, Safra Children’s lymphoma, diagnosed as atypical CLL/SLL, which is charac- ‡ Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel; and Sackler School of terized by recurrent acute waves of active disease (22, 23). The Medicine Tel-Aviv University, Tel-Aviv, Israel patient experienced within 8 years 27 cycles of leukemic waves Received for publication March 9, 2005. Accepted for publication August 9, 2005. followed by spontaneous partial remissions. The first week of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance the wave characterized by fever, generalized lymphadenopathy, with 18 U.S.C. Section 1734 solely to indicate this fact. and increasing number of clonal IgM␬-positive leukemic cells 1 This work was supported by the Carol and Leonora Fingerhut Fund for Cancer usually Ͼ60,000 cells/mm3. After a few days, the symptoms of Research, Tel-Aviv University. the acute illness disappeared. Following 2–3 wk, most of the 2 Address correspondence and reprint requests to Dr. Yael Kaufmann, Institute of transformed leukemic cells disappeared, and the white blood Hematology, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail ad- dress: [email protected] cell count returned to almost a normal level. Nonetheless, 10– 3 G.R. holds the Djerassi Chair in Oncology at Tel Aviv University. 60% of the peripheral lymphocytes were monoclonal B cells. 4 Abbreviations used in this paper: sCD27, soluble CD27; CLL, B cell chronic lym- The remission periods lasted 2–7 mo (22). Transient bouts of phocytic leukemia; RTQ-PCR, real-time quantitative PCR; CM, conditioned medium. serum TNF-␣ and IL-10 preceded the acute phases, which were Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 6941 characterized by coexistence of CD40Lϩ T lymphocytes and Flow cytometry lymphoma cells in the bone marrow (23). During remissions, ϩ For comparison of cell surface marker expression, cells that had been residual IgM␬ leukemic cells exhibited resting phenotype, low cryopreserved during different disease phases were thawed, processed, proliferative response to CD40L, and delayed apoptosis in cul- and analyzed simultaneously. A total of 4 ϫ 105 PBMCs was incubated ture. In contrast, the acute phase counterparts were phenotypi- in 0.4 ml of RPMI 1640 containing 10% FCS for 20 min at 20°C with cally activated, underwent rapid apoptosis, and proliferated CD19 PerCP, CD5 APC, CD27 R-PE, and CD70 FITC, washed in PBS, and analyzed on dual laser FACSCalibur flow cytometer from BD Bio- extensively in response to membrane-anchored CD40L sciences. Discrimination of leukemic cells from the normal hematopoietic (23, 24). cells was done by gating on cells expressing CD19 and CD5. CD70 and The existence of a clonal leukemic cell population throughout CD27 expression on the leukemic cells was scored within the gated ϩ ϩ the course of the disease (22) provides a unique opportunity to CD19 CD5 cells. The following mAbs were used for four-color FACS analysis: R-PE-labeled CD27 clone M-T271 and FITC-labeled CD70 characterize molecular changes in the neoplastic cells associ- (clone Ki-24) (BD Biosciences Pharmingen), allophycocyanin-labeled ated with recurrent activation and regression of the disease. CD5 (clone L17F12), and PerCP-labeled CD19 (BD Biosciences). Microarray analysis of the leukemic cells done in this study Tests of apoptosis and cell proliferation showed consistent pattern of gene expression characterizing different stages of the disease. Because interactions between The patient’s PBMCs or CD19ϩ purified leukemic cells were cultured at 6 CD70 and CD27 provide costimulatory signal in B cell activa- 2 ϫ 10 /ml in RPMI 1640 supplemented by L-glutamine, 10% FCS, and 50 ␮g/ml gentamicin sulfate (conditioned medium (CM)), at 37°C in 5% CO . tion, we examined their involvement in progression of this “cy- 2 Spontaneous apoptosis of the leukemic cells in culture was examined by clic” lymphoma/leukemia. Indeed, CD70 and CD27 were Annexin VFITC staining. A total of 4 ϫ 105 leukemic cells was cultured in among the genes whose expression transiently increased simul- 96-well flat-bottom plates in CM in presence or in absence of 1–9 ␮g/ml Downloaded from taneously with initiation of the acute phase.
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