RESUMO
Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor κB (NF-κB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.
Assuntos
Fatores Reguladores de Interferon/genética , Antígeno Ki-1/metabolismo , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , NF-kappa B/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Genes myc , Células Germinativas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo Genético , Transcrição GênicaRESUMO
Elevated serum levels of the soluble form of IL-2 receptor α (sIL-2Rα) have been correlated with a poor prognosis in a variety of different types of cancers. However, its biologic relevance remains unclear and controversial. In patients with follicular B-cell non-Hodgkin lymphoma (FL), we observed that serum sIL-2Rα levels were elevated compared with controls and that elevated sIL-2Rα levels before treatment were associated with a poor outcome. To explore the mechanism by which sIL-2Rα may contribute to a poor prognosis in FL, we determined the effects of sIL-2Rα on IL-2 signaling and found that the sIL-2Rα-IL-2 complex promoted T-cell differentiation toward to inhibitory T(reg) cells rather than T(H)1 or T(H)17 cells. Shed by activated T cells that express membrane-bound IL-2Rα, sIL-2Rα further enhanced IL-2-mediated phosphorylation of Stat5 thereby significantly up-regulating Foxp3 expression in CD4(+) T cells. We found that CD4(+) T cells treated with either IL-2 or sIL-2Rα-IL-2 complex, but not with sIL-2Rα alone, inhibited the function of CD8(+) T cells. Taken together, these results indicate that sIL-2Rα actually plays an active biologic role in FL by binding IL-2 and promoting IL-2 signaling rather than depleting IL-2 and blocking its function.
Assuntos
Proliferação de Células , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-2/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/mortalidade , Linfoma Folicular/imunologia , Linfoma Folicular/mortalidade , Western Blotting , Estudos de Casos e Controles , Diferenciação Celular , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfoma de Células B/metabolismo , Linfoma Folicular/metabolismo , Fosforilação , RNA Mensageiro/genética , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT5/metabolismo , Taxa de Sobrevida , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
Waldenström macroglobulinemia (WM) is a rare, lymphoplasmacytic lymphoma characterized by hypersecretion of immunoglobulin M (IgM) protein and tumor infiltration into the bone marrow and lymphatic tissue. Our understanding of the mechanisms driving the development and progression of WM is currently by the shortage of representative cell models available for study. We describe here the establishment of a new WM cell line, MWCL-1. Comprehensive genetic analyses have unequivocally confirmed a clonal relationship between this novel cell line and the founding tumor. MWCL-1 cells exhibit an immunophenotype consistent with a diverse, tumor clone composed of both small B lymphocytes and larger lymphoplasmacytic cells and plasma cells: CD3â», CD19âº, CD20âº, CD27âº, CD38âº, CD49Dâº, CD138âº, cIgMâº, and κâº. Cytogenetic studies identified a monoallelic deletion of 17p13 (TP53) in both the cell line and the primary tumor. Direct DNA resequencing of the remaining copy of TP53 revealed a missense mutation at exon 5 (V143A, GTG>GCG). In accordance with primary WM tumors, MWCL-1 cells retain the ability to secrete high amounts of IgM protein in the absence of an external stimulus. The genetic, immunophenotypic, and biologic data presented here confirm the validity of the MWCL-1 cell line as a representative model of WM.
Assuntos
Linhagem Celular Tumoral/fisiologia , Linhagem Celular Tumoral/ultraestrutura , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/patologia , Idoso , Hibridização Genômica Comparativa , Impressões Digitais de DNA , Imunofluorescência , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , MasculinoRESUMO
Although proinflammatory and chemotactic cytokines can profoundly affect the tumor microenvironment, and many of them have been shown to have therapeutic efficacy in preclinical models, the role of these molecules in Waldenström macroglobulinemia (WM) remains poorly understood. In this study, simultaneous analysis of WM patient sera and bone marrow biopsies identified a set of dysregulated cytokines including CCL5, G-CSF, and soluble IL-2 receptor, that were significantly elevated in WM patients whereas IL-8 and EGF levels were significantly lower in these patients compared with healthy controls. Interestingly, CCL5 levels positively correlated with features of disease aggressiveness such as elevated IgM levels and bone marrow involvement. Functional analysis of tumor microenvironment revealed a functional correlation between CCL5 levels and IL-6 levels, a proinflammatory cytokine with an important role in normal and malignant B-cell biology. Furthermore, CCL5 stimulated IL-6 secretion in WM stromal cells resulting in increased IgM secretion by WM malignant cells via the JAK/STAT signaling pathway. Thus, together these results define a novel signaling network in the WM tumor microenvironment controlling IgM secretion and suggest CCL5 as a potential target for the treatment of this disease.
Assuntos
Quimiocina CCL5/imunologia , Interleucina-6/imunologia , Transdução de Sinais/imunologia , Células Estromais/imunologia , Microambiente Tumoral/imunologia , Macroglobulinemia de Waldenstrom/imunologia , Biópsia , Medula Óssea/imunologia , Medula Óssea/metabolismo , Divisão Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Sobrevivência Celular/imunologia , Quimiocina CCL5/sangue , Humanos , Imunoglobulina M/imunologia , Interleucina-6/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Índice de Gravidade de Doença , Células Estromais/citologia , Células Estromais/metabolismo , Macroglobulinemia de Waldenstrom/patologia , Macroglobulinemia de Waldenstrom/terapiaRESUMO
PURPOSE: Transformation of follicular lymphoma is a critical event associated with a poor prognosis. The role of the tumor microenvironment in previous transformation studies has yielded conflicting results. EXPERIMENTAL DESIGN: To define cell subtypes associated with transformation, we examined tissue specimens at diagnosis from patients with follicular lymphoma that later transformed and, using immunohistochemistry (IHC), stained for CD68, CD11c, CD21, CXCL13, FOXP3, PD1, and CD14. Cell content and the pattern of expression were evaluated. Those identified as significantly associated with time to transformation (TTT) and overall survival (OS) were further characterized by flow cytometry and multicolor IHC. RESULTS: Of note, 58 patients were analyzed with median TTT of 4.7 years. The pattern of PD1(+) and CD14(+) cells rather than the quantity of cells was predictive of clinical outcomes. On multivariate analysis, including the follicular lymphoma international prognostic index score, CD14(+) cells localized in the follicle were associated with a shorter TTT (HR, 3.0; P = 0.004). PD1(+) cells with diffuse staining were associated with a shorter TTT (HR, 1.9; P = 0.045) and inferior OS (HR, 2.5; P = 0.012). Multicolor IHC and flow cytometry identified CD14(+) cells as follicular dendritic cells (FDC), whereas PD1(+) cells represented two separate populations, TFH and exhausted T cells. CONCLUSION: These results identify the presence of PD1(+) T cells and CD14(+) FDC as independent predictors of transformation in follicular lymphoma. Clin Cancer Res; 20(11); 2862-72. ©2014 AACR.
Assuntos
Biomarcadores Tumorais/análise , Transformação Celular Neoplásica/patologia , Células Dendríticas Foliculares/patologia , Linfoma Folicular/patologia , Linfócitos T/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Linfoma Folicular/imunologia , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Modelos de Riscos Proporcionais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologiaRESUMO
While the effect of TGF-ß on malignant B cells in non-Hodgkin lymphoma (NHL) has been previously evaluated, studies to specifically define the role of TGF-ß in tumor immunity in B-cell NHL are limited. We found that soluble TGF-ß, secreted by both lymphoma cells and intratumoral T cells, is present in the serum of patients with B-cell NHL. Soluble TGF-ß promoted regulatory T (T(reg)) cells by enhancing expression of Foxp3 in CD4(+) T cells and suppressed effector helper T (T(H)) cells by inhibiting expression of IFN-γ and IL-17. Blockade of the IL-2 signaling pathway diminished the effect of soluble TGF-ß on T cell differentiation. Furthermore, we found that membrane-bound TGF-ß is expressed specifically on the surface of malignant B cells in B-cell NHL. TGF-ß was able to bind to the surface of lymphoma B cells through an interaction with heparan sulfate (HS) but not through the TGF-ß receptor. We showed that pretreatment of lymphoma B cells with TGF-ß significantly inhibits the proliferation and cytokine production of intratumoral T cells. Taken together, these results suggest that tumor-associated soluble and membrane-bound TGF-ß are involved in the regulation of intratumoral T cell differentiation and function in B-cell NHL.
Assuntos
Linfócitos B/citologia , Diferenciação Celular , Membrana Celular/metabolismo , Linfoma não Hodgkin/patologia , Linfócitos T/citologia , Fator de Crescimento Transformador beta/química , Fator de Crescimento Transformador beta/metabolismo , Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Interleucina-2/biossíntese , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Solubilidade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-γ-independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12- and TIM-3-mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients.
Assuntos
Interleucina-12/farmacologia , Linfoma Folicular/patologia , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Interferon gama/biossíntese , Interferon gama/farmacologia , Interleucina-12/biossíntese , Interleucina-12/sangue , Interleucina-12/fisiologia , Estimativa de Kaplan-Meier , Lipopolissacarídeos/farmacologia , Linfoma Folicular/imunologia , Linfoma Folicular/metabolismo , Linfoma Folicular/mortalidade , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Prognóstico , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismoRESUMO
PURPOSE: The TNF receptor superfamily member CD27 is best known for its important role in T-cell immunity but is also recognized as a cell-surface marker on a number of B- and T-cell malignancies. In this article, we describe a novel human monoclonal antibody (mAb) specific for CD27 with properties that suggest a potential utility against malignancies that express CD27. EXPERIMENTAL DESIGN: The fully human mAb 1F5 was generated using human Ig transgenic mice and characterized by analytical and functional assays in vitro. Severe combined immunodeficient (SCID) mice inoculated with human CD27-expressing lymphoma cells were administered 1F5 to investigate direct antitumor effects. A pilot study of 1F5 was conducted in non-human primates to assess toxicity. RESULTS: 1F5 binds with high affinity and specificity to human and macaque CD27 and competes with ligand binding. 1F5 activates T cells only in combination with T-cell receptor stimulation and does not induce proliferation of primary CD27-expressing tumor cells. 1F5 significantly enhanced the survival of SCID mice bearing Raji or Daudi tumors, which may be mediated through direct effector mechanisms such as antibody-dependent cellular cytotoxicity. Importantly, administration of up to 10 mg/kg of 1F5 to cynomolgus monkeys was well tolerated without evidence of significant toxicity or depletion of circulating lymphocytes. CONCLUSIONS: Collectively, the data suggest that the human mAb 1F5, which has recently entered clinical development under the name CDX-1127, may provide direct antitumor activity against CD27-expressing lymphoma or leukemia, independent of its potential to enhance immunity through its agonistic properties.
Assuntos
Anticorpos Monoclonais , Leucemia , Linfoma , Linfócitos T , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Proliferação de Células , Humanos , Leucemia/tratamento farmacológico , Leucemia/imunologia , Linfoma/tratamento farmacológico , Linfoma/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Camundongos Transgênicos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologiaRESUMO
Waldenström macroglobulinemia (WM) is a serious and frequently fatal B-cell malignancy associated with an elevated monoclonal IgM protein in the serum. Many of the mechanisms leading to this disease are not yet known. B-lymphocyte stimulator (BLyS) is a TNF family member that is critical for maintenance of normal B-cell development and homeostasis. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B cells. It also regulates immunoglobulin secretion by normal B cells. To determine the relevance of BLyS in WM, we examined the role of BLyS in WM patient samples. Malignant B cells were found to bind soluble BLyS and variably express the receptors BAFF-R, TACI, and BCMA. We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM. BLyS, alone or in combination with cytokines that induce immunoglobulin production, was found to increase IgM secretion by malignant B cells. Furthermore, BLyS was found to increase the viability and proliferation of malignant B cells from WM patients. Due to the role of BLyS in WM, strategies to inhibit BLyS may potentially have therapeutic efficacy in these patients.
Assuntos
Linfócitos B/fisiologia , Imunoglobulinas/fisiologia , Proteínas de Membrana/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Macroglobulinemia de Waldenstrom/imunologia , Fator Ativador de Células B , Divisão Celular/fisiologia , Linhagem Celular , Citometria de Fluxo , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Macroglobulinemia de Waldenstrom/patologiaRESUMO
PURPOSE: Serum B-lymphocyte stimulator (BLyS) levels have been found to be elevated in a number of immune disease models. Therefore, we sought to establish whether BLyS levels were elevated in patients with B-cell lymphoproliferative disorders and to determine whether elevated BLyS levels correlated with clinical characteristics of the disease. PATIENTS AND METHODS: Specimens were collected from the peripheral blood of individuals diagnosed with B-cell chronic lymphocytic leukemia (B-CLL; n = 70) or from age- and sex-matched patients seen at the same institution (n = 41). Serum BLyS levels were determined by enzyme-linked immunosorbent assay, and sequencing of the BLyS promoter was performed by conventional methods and confirmed by restriction fragment length polymorphism analysis. RESULTS: We found that elevated BLyS levels were more common in patients with familial B-CLL than individuals with sporadic B-CLL or normal controls. Because of this association, we sequenced the BLyS promoter in patients with B-CLL and normal controls and identified a polymorphic site, -871 C/T. We found that the wild-type sequence was significantly underrepresented in patients with familial B-CLL (4%) compared with patients with sporadic B-CLL (30%; P = .01) or controls (24%; P = .04). Furthermore, using a luciferase reporter under control of the BLyS promoter containing either a C or a T at position -871, we found that the reporter construct containing a T at -871 had a 2.6-fold increase in activity (P = .004). CONCLUSION: Our data suggest serum BLyS levels are elevated in patients with familial B-CLL and that elevated BLyS levels correlate with the presence of a T at -871 in the BLyS promoter.
Assuntos
Biomarcadores Tumorais/sangue , Leucemia Linfocítica Crônica de Células B/sangue , Linfoma de Células B/sangue , Proteínas de Membrana/sangue , Adulto , Idoso , Fator Ativador de Células B , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Células HL-60 , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Linfoma de Células B/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Fator de Necrose Tumoral alfa/genéticaRESUMO
We have earlier shown that attenuated measles virus (MV) has therapeutic potential as a replicating oncolytic virus in models of non-Hodgkin's lymphoma (NHL). In the current study, we investigated whether we could obtain replicating MVs capable of entering CD20(+) target cells through an interaction between a single-chain (scFv) anti-CD20 antibody and the CD20 antigen, a target of considerable clinical relevance in NHL. We replaced the H envelope glycoprotein of MV by an H-scFv anti-CD20 fusion protein with and without a protease-cleavable linker. Biochemical analysis of purified virions confirmed that the modified H proteins were incorporated into the viral particles with efficiency similar to unmodified H. Experiments employing CHO cells and CHO cells expressing human CD20 indicated that the MVH alpha CD20 viruses were able to replicate well in CHOCD20 but not CHO cells. MVH alpha CD20 or a nonmodified control MV were administered systemically to immunodeficient mice bearing bilateral human tumor xenografts, one side with and the other side without CD20 expression. Growth of CD20(+) tumors was retarded by MVH alpha CD20 as compared with the control virus. The viruses had equivalent effects on the CD20(-) tumors. Thus we have demonstrated that the entry of a replicating oncolytic virus can be mediated through an interaction between a highly clinically relevant single-chain antibody and its target antigen, and we have shown that this interaction enhances in vivo oncolytic activity.
Assuntos
Antígenos CD20/imunologia , Vírus do Sarampo/fisiologia , Sequência de Aminoácidos , Animais , Antígenos CD20/genética , Células CHO , Fusão Celular , Chlorocebus aethiops , Cricetinae , Citometria de Fluxo , Engenharia Genética , Região Variável de Imunoglobulina/genética , Vírus do Sarampo/genética , Dados de Sequência Molecular , Células VeroRESUMO
BLyS, recently shown to be critical for survival of normal B cells, has been found to be elevated in a number of immune disease models. A role for BLyS in the survival of malignant B cells has also been revealed and we therefore sought to identify a role for BLyS and its receptors in non-Hodgkin lymphoma (NHL). We found that tumor cells from all NHL histologic subtypes expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern of expression was variable. We provide evidence that BLyS is expressed in tumors from patients with NHL and that BLyS levels increase as tumors transform to a more aggressive phenotype. Additionally, we provide evidence that serum BLyS levels are elevated in a subgroup of patients with NHL. In patients with de novo large B-cell lymphoma, a high BLyS level correlated with a poorer median overall survival, the presence of constitutional symptoms, and elevated values of lactic dehydrogenase. When BLyS levels were correlated with response to therapy in all patients, responding patients had a significantly lower BLyS level than those with progressive disease. In summary, we found that BLyS and its receptors represent a potentially important therapeutic target in B-cell lymphoma.