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Survival Response to B-Cell Receptor Ligation Is Restricted to Progressive Chronic Lymphocytic Leukemia Cells Irrespective of Zap70 Expression

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Survival Response to B-Cell Receptor Ligation Is Restricted to Progressive Chronic Lymphocytic Leukemia Cells Irrespective of Zap70 Expression Research Article Survival Response to B-Cell Receptor Ligation Is Restricted to Progressive Chronic Lymphocytic Leukemia Cells Irrespective of Zap70 Expression Pierre-Antoine Deglesne,1 Nathalie Chevallier,2 Re´mi Letestu,1 Fanny Baran-Marszak,1 TaoufikBeitar, 1 Ce´lia Salanoubat,3 Laurence Sanhes,3 Joelle Nataf,3 Claudine Roger,1 Nadine Varin-Blank,2 and Florence Ajchenbaum-Cymbalista1 1Unite Propre de Recherche de l’Enseignement Superieur EA-3406, Hopital Avicenne Universite´ Paris 13 Bobigny; 2U567 Institut National de la Sante et de la Recherche Medicale, Unite´Mixte de Recherche 8104 Centre National de la Recherche Scientifique, Universite´Paris V, Institut Cochin, Department of Hematology; and 3Institut National de la Sante et de la Recherche Medicale E0355, Hotel Dieu, Paris, France Abstract disease over years with no need of treatment. A number of Despite very similar gene expression profiles, the clinical biological features have been identified that seem to have course of B-cell chronic lymphocytic leukemia (B-CLL) is prognostic value, such as lymphocyte doubling time (LDT) heterogeneous. Immunoglobulin VH (IgVH) mutational status measurement, serum thymidine kinase level, mutational status of and expression of B-cell receptor (BCR) signaling mediators the expressed immunoglobulin heavy-chain variable-region (IgVH) have been associated with disease progression. However, the genes, and Zap70 tyrosine kinase expression (1–4). consequences of BCR engagement on cell survival and Patients with CLL cells expressing unmutated IgVH ‘‘unmutated evolution of the disease remain unclear. We show here that CLL’’ have a significantly more aggressive clinical course and worse B-CLL cell survival is dependent on the threshold of BCR outcome when compared with those expressing IgVH with >2% stimulation induced by immobilized antibody, in contrast to somatic mutation ‘‘mutated CLL’’ (5). These observations led to the soluble anti-M F(ab)¶2 antibody, which leads to apoptosis. hypothesis that B-cell receptor (BCR) activation could play a Measurement of metabolic activity and apoptotic response central role in the physiopathology of the disease. The use of a discriminated two subgroups. ‘‘Nonresponders’’ showed low biased VH gene repertoire and the presence of nonrandom VDJ metabolic activity and unmodified apoptotic response upon combinations further support a role for antigenic stimulation in BCR stimulation. In contrast,‘‘responders’’ exhibited increased the selection of the malignant clone (6–9). Moreover, gene profiling metabolic activity and inhibition of spontaneous apoptosis. studies comparing mutated and unmutated CLL cases distin- This survival advantage was associated to a BCR-dependent guished the differential expression of a small subset of genes activation profile leading to induction of cyclin D2/cyclin- pointing to BCR signaling pathways (10, 11). BCR signaling is critical for B-lymphocyte development, dependent kinase 4 (cdk4) expression and G1 cell cycle progression. The ability to respond to BCR ligation correlated proliferation, and survival. In animal models, a strong BCR signal + with an unfavorable clinical course and allowed to define an is responsible for the specific expansion of CD5 B cells compared additional group of patients among IgVH-mutated cases with normal B subtypes (12). Mice lacking or overexpressing exhibiting a risk of progression. Remarkably, we show that various regulatory effectors of the BCR signaling pathways Zap70 expression was neither mandatory nor sufficient to reproduce phenotypes with B-cell CLL (B-CLL) features. Notably, À/À À/À À/À À/À generate downstream survival signals and cyclin D2/cdk4 CD19 , Btk , cyclin D2 ,orvav1 animals exhibit a + up-regulation. In conclusion, BCR engagement has a signifi- depletion in CD5 B-cells whereas CD19 transgenic animals show cant effect on B-CLL cell survival, activation, and G1 an expansion of this compartment (13–16). One of the BCR progression. Furthermore, our results provide new insights signaling targeted events is the induction of cyclin D2 expression, in the physiopathology of progressive IgVH-mutated cases. which was shown to be specifically required in BCR-induced, but (Cancer Res 2006; 66(14): 7158-66) not CD40 ligand– or lipopolysaccharide-induced proliferation (17). Moreover, lack of cyclin D2 induction and subsequent cell cycle Introduction progression in response to BCR cross-linking has been associated with defects in activation pathway intermediates (15, 18, 19). Chronic lymphocytic leukemia (CLL) is characterized by the + Early events in the activation of the BCR involve the recruitment accumulation of slowly dividing CD5 B lymphocytes. The clinical and subsequent phosphorylation of various enzymes, including course of CLL is heterogeneous. Some patients progress rapidly members of Src and Syk families of tyrosine kinases (20). Until and require early chemotherapy whereas others exhibit a stable recently, Zap70, the second member of the Syk family, was described as being specifically expressed in T cells and natural killer (NK) cells whereas its counterpart Syk was shown to function Note: P-A. Deglesne and N. Chevallier contributed equally to this work. in the BCR signalosome (21). Interestingly, transcriptional studies Requests for reprints: Florence Ajchenbaum-Cymbalista, Hematology have identified Zap70 expression in CLL cells with absence of Department, Hopital Avicenne Bobigny, France. E-mail: [email protected] somatic mutations ‘‘unmutated CLL’’ (10, 11, 22, 23). Zap70 was hop-paris.fr or Nadine Varin-Blank, U567 Institut National de la Sante et de la Recherche Medicale, Unite´Mixte de Recherche 8104 Centre National de la Recherche associated to membrane immunoglobulin/CD79b complexes on Scientifique, Universite´Paris V, Institut Cochin, Department of Hematology, Paris, IgM ligation, which was interpreted to contribute to the enhanced France. Phone: 33-1-40-51-65-40; Fax: 33-1-40-51-65-10; E-mail: [email protected]. I2006 American Association for Cancer Research. response to BCR stimulation observed preferentially in unmutated doi:10.1158/0008-5472.CAN-06-0085 CLL cases (24–26). Those results also suggested that signaling Cancer Res 2006; 66: (14). July 15, 2006 7158 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2006 American Association for Cancer Research. Survival Response to BCR Ligation in B-CLL Cells through BCR could differ in nature and intensity depending on the anti-Vav1 monoclonal antibody from Abcam (Cambridge, United King- immunoglobulin mutational status (27–29). dom). Detection was done with enhanced chemiluminescence plus However, it remained unclear whether antigenic stimulation may reagent (Amersham Biosciences Europe, Freiburg, Germany). play a critical role in the progression and maintenance of the disease. In the present study, we evaluated, therefore, the responsiveness to BCR stimulation and showed that B-CLL cell Results survival depends on the threshold of BCR stimulation. BCR Both anti-IgM and anti-M F(ab)¶2 immobilized antibodies signaling promoted in vitro B-CLL cell survival and G1 progression promote B-CLL cell survival. To investigate the effect of BCR leading to cyclin D2/cyclin-dependent kinase 4 (cdk4) up- engagement on B-CLL cell survival in vitro, we standardized our regulation in a subset of patients with progressive disease and stimulation procedures by measurement of the metabolic mito- unfavorable prognostic factors only. In contrast, BCR stimulation chondrial activity using MTS assay. Freshly isolated B-CLL cells had no effect on cells from patients with stable disease. Moreover, from five patients were stimulated with immobilized anti-IgM for this analysis allowed the identification of a group of progressive various periods of time and compared with unstimulated cells. patients exhibiting mutated IgVH and lack of expression of Zap70 B-CLL cell survival, monitored at a given concentration of 10 Ag/ tyrosine kinase. mL of antibody, indicated that the best discriminating kinetic study was achieved after 72 hours of culture (Fig. 1A). At this reference time, maximal antibody dose response was reached with 5 Ag/mL Materials and Methods and remained stable up to 10 Ag/mL of immobilized anti-IgM CLL samples. Peripheral blood mononuclear cells were obtained from (Fig. 1B). Consequently, all further assays were set up at 72 hours of 58 untreated CLL patients after informed consent. The diagnosis of CLL cell culture in the presence of 10 Ag/mL of immobilized anti-IgM. was ascertained by both typical morphology and immunophenotype as The effect of immobilized anti-IgM was then compared with those evidenced by Royal Marsden Hospital score >4. of soluble or immobilized anti-A F(ab)¶2 stimulations. Interestingly, Cell isolation and culture. B lymphocytes from patients were separated soluble anti-A F(ab)¶2 antibody stimulation resulted in decreased by Roset Sep kit according to the recommendation of the manufacturer, MTS ratio in all cases, indicative of a proapoptotic process followed by Ficoll-Hypaque density gradient (Stem Cell Technologies, (Fig. 1C). In contrast, immobilized anti-A F(ab)¶2 antibody, similarly Grenoble, France). All further experiments were done with these freshly to IgG anti-A but to a lesser extent, restored B-CLL cell survival isolated cells. Purity was verified by flow cytometry; contaminating T lymphocytes and NK cells were always <2%. B-CLL cells were cultured at with positive MTS ratio. Quantitation of the
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