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The Journal of Immunology, 2006, 176: 5715-5719.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Constitutive B Cell Receptor Signaling Is Critical for Basal Growth of B Lymphoma1

Murali Gururajan*,{ddagger}, C. Darrell Jennings and Subbarao Bondada2,*,{dagger},{ddagger},§,¶

* Department of Microbiology, Immunology and Molecular Genetics, {dagger} Sanders Brown Center on Aging, University of Kentucky, {ddagger} Graduate Center for Toxicology, § Markey Cancer Center, and Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
B lymphomas account for the majority of the lymphoma cases. BCR expression appears to be important for B lymphoma because most oncogenes are translocated to nonrearranged Ig loci and because all of the variants that arise in anti-idiotypic Ab-treated lymphoma patients remain BCR positive. Based on this and the fact that BCR is required for mature B cell survival, we tested the requirement for continued expression of BCR for the growth and survival of B lymphoma cells. Using Ig{alpha} or Igbeta-specific small interfering RNA (siRNA) to inhibit BCR expression, we demonstrate for the first time that constitutive signaling by BCR is critical for survival and proliferation of both murine and human B lymphoma cells. The BCR signals in lymphoma appear to be mediated by Syk, as it is constitutively active in a variety of B lymphoma cells. Blocking Syk activity by selective inhibitors suppresses growth of several murine and human B lymphomas.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Non-Hodgkin’s lymphoma accounts for the majority of the lymphoma-related cases. Diffuse large cell lymphoma (DLBCL)3 is the most common non-Hodgkin’s lymphoma. B lymphomas develop primarily due to chromosomal translocations. Bcl-6, a key transcription factor required for the germinal center reaction, is translocated in ~35% of the DLBCL patients (1). All of these B lymphomas express BCR, but the role of BCR in the survival and basal growth of these lymphoma cells is unknown.

B cell development occurs as distinct steps in the bone marrow and concludes when a B cell precursor successfully rearranges Ig H and L chain genes expressing a functional surface Ag receptor. Cells that express a functional BCR differentiate into mature naive B cells and leave the bone marrow, whereas B cell precursors that fail to express a BCR undergo apoptosis (2, 3, 4). Ig{alpha} and Igbeta molecules in the BCR complex are critical for signaling via the ITAMs present in their cytoplasmic domains. ITAMs transmit signals that lead to activation of several tyrosine kinases upon BCR cross-linking. BCR cross-linking leads to activation of protein tyrosine kinases, the Src family kinase Lyn, the (spleen tyrosine kinase (Syk) kinase, and the Tec family kinase, Bruton’s tyrosine kinase. The recognition of Ag by BCR leads to B cell proliferation, and in the presence of additional signals (Th cell-derived cytokines) leads to B cell differentiation into Ab-secreting plasma cells. The question of whether basal BCR signaling is essential for maintenance of peripheral mature B cells was recently addressed. Using a conditional transgenic mouse model, Kraus et al. (5) demonstrated that removal of surface BCR in resting mature B cells results in apoptosis and loss of such cells in the periphery. Moreover, introduction of mutations in the Ig{alpha} cytoplasmic ITAMs in an inducible and cell stage-restricted manner leads to loss of mature B cells (5).

Most of the B cell lymphomas of the non-Hodgkin’s type (widely prevalent type) express surface BCR. Interestingly, follicular lymphoma patients that are treated with anti-idiotypic Abs develop Id-negative variants, all of which continue to express BCR. No BCR-negative variants have been observed, suggesting that BCR expression may be important for B lymphomas (6). Consistent with this notion is the finding that most chromosomal translocations involving oncogenes always occur in the nonproductively rearranged Ig loci with a few exceptions (6). Also, a role for Ag-induced signaling is suggested by the strong association between Helicobacter pylori infection and B lymphoma (6). These data could be interpreted as BCR having a role in B lymphoma development but not maintenance. However, recently (7) we showed that even Burkitt’s lymphoma cells that have the c-myc oncogenes translocated into the Ig locus required JNK-mediated signals for c-myc expression and survival, suggesting a role for BCR signals in growing lymphoma cells. These data led us to hypothesize that the basal BCR signaling is essential for survival and proliferation of B lymphoma cells. Using Ig{alpha}- or Igbeta-specific small interfering RNA (siRNA) to inhibit surface BCR expression, we demonstrate for the first time that constitutive BCR signaling is critical for basal growth of B lymphoma. Previously, it has been shown (6, 8, 9) that BCR ligation-induced signaling promotes the survival of chronic lymphocytic leukemia and hairy cell leukemia, though the role of basal signaling was not examined. The primary role of BCR signaling appears to be to activate Syk, a non-Src protein tyrosine kinase expressed in B cells. Syk was constitutively activated in several B lymphoma cell lines and in primary B lymphoma samples, and its activation was inhibited when BCR expression was reduced by Ig{alpha}-specific siRNA. Furthermore, inhibition of Syk activation with a chemical inhibitor suppressed B lymphoma growth.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Reagents, mice, and cell lines

Piceatannol (trans-3,3',4,5'-tetrahydroxystilbene), selective Syk inhibitor, (Calbiochem), was dissolved in DMSO and diluted to 2 mM in culture medium. All reagents and cell lines were obtained as described earlier (7). BKS-2 and CH31 (murine B lymphoma cell lines) and SUDHL-4, SUDHL-6, and OCI-Ly10 (human DLBCL cell lines) were cultured as described earlier (7).

Cell viability, proliferation, and cell cycle assays

To measure proliferation, 2 x 104 cells were cultured in 200 µl of medium supplemented with 10% FCS. After 44 h (66 h for human cells), the cultures were pulsed for 4 or (6 h for human) with 1µCi thymidine (DuPont/NEN), and the incorporated radioactivity was measured as described previously (7). Statistical significance of different treatments was evaluated by the Student’s t test. The viability and cell cycle status were respectively analyzed by the trypan blue dye exclusion method and by staining with Hoechst 33342 as described earlier (7).

Transfection of siRNA and plasmids into B lymphoma cells

Transfection of B lymphoma cells with GFP plasmid and siRNA was done as described earlier (7). Hoechst staining of GFP+ cells was analyzed 48 h after transfection for cell cycle profile by a MoFlo flow cytometer (DakoCytomation). The sequence of murine Ig{alpha}-specific siRNA is 3'-CUUGAUGACUGUUCUAUGUUU-5' and 5'-PACAUAGAACAGUCAUCAAGUU-3'. For human Ig{alpha}-specific siRNA, it is 3'-CAUAGGAGAUGUCCAGCUGUU-5' and 5'-PCAGCUGGACAUCUCCUAUGUU-3'. The sequence of murine Igbeta-specific siRNA is 3'-GCACUGACCUGGUUCCGAAUU-5' and 5'-PUUCGGAACCAGGUCAGUGCUU-3' and for murine CD44-specific siRNA is 3'-GCAGAUCGAUUUGAAUGUAUU-5' and 5'-PUACAUUCAAAUCGAUCUGCUU-3. All siRNAs were obtained from Dharmacon. The transfection efficiency of murine B lymphoma cells was 20–25% and that of human lymphoma cells was 70–80%.

Immunoprecipitation, Western blotting, and flow cytometry

Cell lysates were prepared in 1x SDS sample buffer or 1% Triton X-100 as described earlier and were subjected to SDS-PAGE and Western blot analysis (7). B lymphoma cells were stained with IgM-PE (BD Biosciences) and analyzed by FACS.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
BCR is constitutively active in B lymphoma cells and inhibiting its expression represses B lymphoma growth

Basal BCR signaling was shown to signal cell survival in normal resting mature B cells in the periphery (5). In contrast to normal B cells, malignant B cells or lymphomas are actively in cell cycle, in part due to chromosomal translocations of cell survival and or cell proliferation genes leading to their deregulated expression. We first tested whether BCR was constitutively active in B lymphoma cells. We found that Ig{alpha}, a key component of BCR complex was constitutively tyrosine phosphorylated in three different B lymphoma cells (Fig. 1A, top left panel). In contrast, naive B cells demonstrated very low levels of Ig{alpha} tyrosine phosphorylation. We next investigated whether this apparent constitutive BCR signaling is required for the maintenance of B lymphoma growth. Partial ablation of surface BCR expression was achieved using siRNA that specifically targets Ig{alpha} as shown by a decrease in the Ig{alpha} levels determined by Western blotting (Fig. 1A, top right panel) and by a decrease in the mean fluorescence intensity of surface IgM on BKS-2 and CH31 (Fig. 1A, bottom panels) and IgG on SUDHL-4 B lymphoma (data not shown). The surface expression of B220 and CD40 on both control and Ig{alpha} siRNA-treated lymphoma cells remained comparable. Interestingly, treatment with siRNA specific for Ig{alpha} altered the cell cycle progression of the B lymphoma cells. Cycling (S phase) cells decreased from 30 ± 2 in control siRNA treated to 15 ± 1 (mean ± SD of five experiments) in Ig{alpha} siRNA-treated BKS-2 B lymphoma cells (Fig. 1B). In contrast, the G1 cells increased from 40 ± 3 in control siRNA treated to 65 ± 4 in Ig{alpha} siRNA-treated BKS-2 B lymphoma cells (Fig. 1B). Cycling (S phase) and G1 phase cells changed from 30 ± 3 and 50 ± 2 in control siRNA treated to 18 ± 2 and 68 ± 1 (mean ± SD of two experiments) in Ig{alpha} siRNA-treated SUDHL-4 B lymphoma cells, respectively (Fig. 1C). Similar response was observed in SUDHL-6 B lymphoma. This reduction in cycling cells was also confirmed by thymidine incorporation in BKS-2 and SUDHL-4 cells (Fig. 1D). Moreover, we observed a significant decrease in viable cells as well as total cell counts as measured by trypan blue staining (Fig. 1E). Alternatively, knocking down surface Ig with Igbeta-specific siRNA induced a decrease in BCR expression accompanied by growth inhibition similar to the Ig{alpha} approach. Cycling (S phase) and G1 phase cells changed from 24 ± 1 to 41 ± 2 in control siRNA treated to 18 ± 1 and 55 ± 1 (mean ± SD) in Igbeta siRNA-treated BKS-2 B lymphoma cells, respectively. Based on these observations, we conclude that BCR is constitutively active in B lymphoma and partially knocking down its expression correlates with altered proliferation patterns and survival of the treated cells.


Figure 1
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  		FIGURE 1. Constitutive phosphorylation of cytoplasmic domain of BCR (Ig{alpha}) in B lymphomas and the effect of partial ablation of BCR on B lymphoma growth. A, top panel, Ig{alpha} was immunoprecipitated from B lymphoma cell lysates and the immunoprecipitates were analyzed by immunoblotting with an Ab to phosphotyrosine which were then stripped and probed for Ig{alpha}. Bottom panels, BKS-2 and CH31 B lymphoma cells were transfected and cultured for 48 h with a GFP plasmid and control siRNA or Ig{alpha} siRNA and stained for IgM expression and analyzed for GFP+ cells by flow cytometry. The mean fluorescence intensity of IgM expression for control vs Ig-{alpha} siRNA-treated cells was 1497 ± 100 vs 728 ± 50 for BKS-2 and 944 ± 40 vs 425 ± 25 for CH31, respectively. The x-axis of the histograms is plotted on a log scale. Histogram representation of Hoechst staining of BKS-2 B lymphoma (B) and SUHDL-4 (C) in the presence of control siRNA or Ig{alpha} siRNA. Percentages indicate GFP+ cells in different phases of the cell cycle. D, Proliferation of BKS-2 and SUDHL-4 B lymphoma cells treated with control siRNA or Ig{alpha} siRNA for 48 h as measured by thymidine incorporation. Results are expressed as mean ± SE of triplicate cultures for each treatment. Experiments were performed two to five times with similar outcome. *, p < 0.01 when response with Ig{alpha} siRNA is compared with control siRNA. E, Viability (top panel) and total cell numbers (bottom panel) of BKS-2 B lymphoma cells treated with control siRNA or Ig{alpha} siRNA for 48 h in four independent experiments. F, Tritiated thymidine incorporation in BKS-2, CH12.Lx, SUDHL-4, and RAJI B lymphoma cells treated with varying doses of IFN-{alpha} for 2 days. Results are representative of two experiments.

 
Next, we tested whether the growth inhibitory effects of BCR ablation were reversible. A variety of secreted cytokines (e.g., IL-4, IL-10) could act in an autocrine manner, promoting B lymphoma growth. As shown in Table I, IL-4 but not IL-10 substantially reversed the inhibitory effects upon B lymphoma cell cycle progression induced by Ig{alpha} siRNA treatment.


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  		Table I. Cell cycle analysis of BKS-2 B lymphoma cells treated with control or Ig{alpha} siRNA in the presence or absence of IL-4 or IL-10 for 48 ha

 
Signaling through TLR by dsRNA can trigger IFN-{alpha} production which might be growth inhibitory to B lymphoma cells (10). We addressed the role of IFN-{alpha} in this experimental system by using four different control siRNAs. Two of the control siRNAs had the same GC content as the Ig{alpha} siRNA but were not known to target any mammalian target, the third one targeted CD44, a cell adhesion molecule, and the fourth one targeted CD86, a costimulatory molecule. All four control siRNAs neither decreased BCR expression nor induced B lymphoma growth arrest (data not shown). Moreover, exogenous addition of different doses of IFN-{alpha} over a three-log range did not affect B lymphoma cell expansion as measured by thymidine incorporation (Fig. 1F). As a positive control, we used the RAJI Burkitt’s B lymphoma cell line (Fig. 1F), which was sensitive to growth inhibition caused by IFN treatment in agreement with previously published studies (11).

BCR-mediated signal transduction is down-modulated upon inhibition of surface BCR expression

Consistent with constitutive BCR signaling, Syk, an upstream component of the BCR complex was phosphorylated, which was reduced upon knocking down Ig{alpha} expression (Fig. 2, top left panel). This was accompanied by a decrease in tyrosine phosphorylation of BLNK, a direct target of Syk (Fig. 2, bottom panel). Phosphorylated JNK (Fig. 2, top left panel) and Akt and cellular levels of early growth response gene-1 (Egr-1), Bcl-xL, and cyclin D2 were also down-regulated in these cells (Fig. 2, top right panel). These results predicted a critical role for BCR-derived trophic (Akt, Egr-1, and Bcl-xL) and proliferation (cyclin D2) signals in the continued expansion and survival of B lymphoma cells. The concept of ligand-independent BCR signaling was indirectly supported by the observations that pervanadate induced phosphorylation of upstream components of BCR signaling machinery like Syk and Lyn in BCR-negative myeloma cell lines, only when they are reconstituted with BCR (12). Moreover, it was demonstrated that introduction of a retrovirus expressing the Ig{alpha} ITAM domains in precursor bone marrow cells led to the appearance of mature B cells in the periphery of RAG–/– mice (13).


Figure 2
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  		FIGURE 2. Signaling components downstream of the BCR complex are down-regulated upon partial ablation of surface BCR by RNA interference. BKS-2 (top left and right panels) or SUDHL-4 (bottom panel) B lymphoma cells were incubated with control siRNA or Ig{alpha} siRNA for 48 h and cell lysates were prepared. Cell lysates were analyzed by immunoblotting with Abs to pSyk, pJNK, pAkt, Bcl-x, cyclin D2, and Egr-1, which were then stripped and probed for JNK, Akt, and beta-actin. BLNK was immunoprecipitated from SUDHL-4 cell lysates and probed for phosphotyrosine (ptyr) of BLNK. The densitometric ratio of cyclin D2:actin is 2.6 for control siRNA and 1.7 for Ig{alpha} siRNA and that of ptyr of BLNK to BLNK is 3.0 for control siRNA and 1.9 for Ig{alpha} siRNA-treated cells. Results are representative of two experiments.

 
Syk, an upstream component of BCR signaling pathway is constitutively active in B lymphoma cells and targeting Syk with an inhibitor suppresses B lymphoma growth

Fig. 3A demonstrates that several B lymphoma cells (long-term cell lines and primary isolates) expressed constitutively active Syk in contrast to normal splenic and PBMC B cells. When CH31, SUDHL-4 (Fig. 3B), BKS-2, and OCI-Ly10 (data not shown) B lymphoma cell lines were treated with piceatannol, a Syk inhibitor, there was a dose-dependent reduction in the basal proliferation compared with vehicle-treated cells (Fig. 3B) (14). These results demonstrate that constitutively active Syk is required for B lymphoma growth and that activation is BCR dependent. Nevertheless, Syk is also shown to be activated by stimulation with LPS, integrin, and chemokines (15, 16, 17), suggesting that the effects of Syk inhibitor may involve blocking of Syk activation induced by BCR-dependent and -independent signals. Syk induces multiple signaling pathways including PI3K, NF-{kappa}B, phospholipase C-{gamma}, and JNK (18), all of which can be down-regulated by targeting Syk.


Figure 3
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  		FIGURE 3. Constitutive Syk phosphorylation and the effect of its suppression on B lymphoma growth (A). A variety of B lymphoma cell lines and tumors from both murine and human origin express the phosphorylated form of Syk constitutively. Mouse primary tumors are B lymphomas isolated from Eµ-Myc transgenic mice. Human primary B lymphomas include small cell lymphoma (SCL), follicular cell lymphoma (FCL), and Burkitt’s lymphoma (BL) which are characterized by flow cytometry. Experiments were performed two to four times with similar results. B, CH31 (left panel) and SUDHL-4 (right panel) B lymphoma cells were incubated with medium, different doses of Syk inhibitor (piceatannol) or vehicle (DMSO) alone for 2 days, and proliferation was measured. Results are expressed as mean ± SE of triplicate cultures. Experiments were done two to three times with similar results. *, p < 0.01 when response with Syk inhibitor is compared with the vehicle.

 
In summary, our data demonstrate for the first time that BCR is constitutively active in B lymphoma cells leading to constitutive activation of Syk and that partial ablation of surface BCR with siRNA or suppression of Syk with a specific inhibitor induced growth arrest. Using curcumin to inhibit Syk, we have also shown that Syk activation is important in vivo for the growth of BKS-2 B lymphoma cells (M. Gururajan T. Dasu, S. Shahidain, C. D. Jennings, V. M. Rangnekar, and S. Bondada, manuscript in preparation). Thus, we demonstrate that constitutive signaling by BCR is essential for survival and proliferation of B lymphoma cells. It is likely that BCR is signaling in lymphoma cells in a ligand-independent manner but the underlying mechanism is unknown. One possibility is that in lymphoma, BCR constitutively associates with lipid rafts that have been shown to be critical for BCR signaling, whereas such raft association of BCR is induced in normal B cells by BCR ligation (13, 19). The other possibility is oxidative stress, which has been shown to induce Syk activation in B lymphoma cells. Using a reverse genetics approach to reconstitute proximal BCR components in the Drosophila cell system, Rolli et al. (20) demonstrated that Syk phosphorylates both the tyrosines of the ITAMs of the BCR. It is also conceivable that certain mutations in Ig{alpha} and/or Igbeta allow such constitutive signaling in lymphoma cells. Our findings have clinical implications, because they have identified multiple targets that can be used to develop novel therapeutics to treat B lymphoma. Also, our observations point out for the first time that constitutive BCR signaling might be important for the maintenance of basal B cell malignancy in addition to genetic alterations in oncogenes.


   Acknowledgments
 
We thank Jennifer Strange and Greg Bauman for flow cytometry. We also thank Drs. Snow and Kaplan for critical reading of this manuscript.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
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 with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grants AI 21490, AG 05731, and CA 92372 (to S.B.). Back

2 Address correspondence and reprint requests to Dr. Subbarao Bondada, University of Kentucky, Center on Aging, Sanders Brown Building, Room 329A, Lexington, KY 40536-0230. E-mail address: bondada{at}uky.edu Back

3 Abbreviations used in this paper: DLBCL, diffuse large cell lymphoma; Syk, spleen tyrosine kinase; siRNA, small interfering RNA; Egr-1, early growth response gene-1. Back

Received for publication January 24, 2006. Accepted for publication March 8, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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