Marginal-Zone B Cells in the Human Lymph Node and Spleen Show Somatic Hypermutations and Display Clonal Expansion

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 226-234 ◽  
Author(s):  
Anne Tierens ◽  
Jan Delabie ◽  
Lieve Michiels ◽  
Peter Vandenberghe ◽  
Chris De Wolf-Peeters
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
Clonal Expansion ◽  
Germinal Centers ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Marginal Zone B Cells ◽  
Vh Genes

Splenic marginal-zone B cells, marginal-zone B cells of Peyer’s patches in the gut, and nodal marginal-zone B cells (also identified as monocytoid B cells) share a similar morphology and immunophenotype. These cells likely represent a distinct subset of B cells in humans and rodents, but their precise ontogenetic relationship as well as their origin from B cells of the germinal center is still debated. To study this, we performed a mutation analysis of the rearranged immunoglobulin variable genes (VH) of microdissected single nodal and splenic marginal-zone cells. In addition, we investigated the presence of proliferating cells and B-cell clones in the human splenic and nodal marginal zone as well as adjacent germinal centers. This was performed by immunohistochemical staining for the Ki-67 antigen and denaturing gradient gel analysis of amplified immunoglobulin heavy chain genes’ complementarity determining region 3 of microdissected cell clusters. A variable subset of nodal and splenic marginal-zone B cells showed somatic mutations in their rearranged VH genes, indicating that both virgin and memory B cells are present in the nodal and splenic marginal zone. Nodal and splenic marginal-zone B cells preferentially rearranged VH3 family genes such as DP47, DP49, DP54, and DP58. A preferential rearrangement of the same VH genes has been shown by others in the peripheral CD5− IgM+ B cells. These data suggest that the splenic and nodal marginal-zone B cells are closely related B-cell subsets. We also showed that marginal-zone B cells may cycle and that clones of B cells are frequently detected in the nodal as well as the splenic marginal zone. These clones are not related to those present in adjacent germinal centers. These data favor the hypothesis that clonal expansion occurs in the marginal zone. Whether the somatic hypermutation mechanism is activated during the clonal expansion in the marginal zone and which type of immune response triggers the clonal expansion need to be elucidated.

Marginal-Zone B Cells in the Human Lymph Node and Spleen Show Somatic Hypermutations and Display Clonal Expansion

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 226-234 ◽  
Author(s):  
Anne Tierens ◽  
Jan Delabie ◽  
Lieve Michiels ◽  
Peter Vandenberghe ◽  
Chris De Wolf-Peeters
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
Clonal Expansion ◽  
Germinal Centers ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Marginal Zone B Cells ◽  
Vh Genes

Abstract Splenic marginal-zone B cells, marginal-zone B cells of Peyer’s patches in the gut, and nodal marginal-zone B cells (also identified as monocytoid B cells) share a similar morphology and immunophenotype. These cells likely represent a distinct subset of B cells in humans and rodents, but their precise ontogenetic relationship as well as their origin from B cells of the germinal center is still debated. To study this, we performed a mutation analysis of the rearranged immunoglobulin variable genes (VH) of microdissected single nodal and splenic marginal-zone cells. In addition, we investigated the presence of proliferating cells and B-cell clones in the human splenic and nodal marginal zone as well as adjacent germinal centers. This was performed by immunohistochemical staining for the Ki-67 antigen and denaturing gradient gel analysis of amplified immunoglobulin heavy chain genes’ complementarity determining region 3 of microdissected cell clusters. A variable subset of nodal and splenic marginal-zone B cells showed somatic mutations in their rearranged VH genes, indicating that both virgin and memory B cells are present in the nodal and splenic marginal zone. Nodal and splenic marginal-zone B cells preferentially rearranged VH3 family genes such as DP47, DP49, DP54, and DP58. A preferential rearrangement of the same VH genes has been shown by others in the peripheral CD5− IgM+ B cells. These data suggest that the splenic and nodal marginal-zone B cells are closely related B-cell subsets. We also showed that marginal-zone B cells may cycle and that clones of B cells are frequently detected in the nodal as well as the splenic marginal zone. These clones are not related to those present in adjacent germinal centers. These data favor the hypothesis that clonal expansion occurs in the marginal zone. Whether the somatic hypermutation mechanism is activated during the clonal expansion in the marginal zone and which type of immune response triggers the clonal expansion need to be elucidated.

Analysis of IgVH, BCL-6, PIM, RHO/TTF and PAX5 Mutational Status in Splenic and Nodal Marginal Zone B Cell Lymphoma Suggests a Particular B Cell Origin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 162-162 ◽  
Author(s):  
Alexandra Traverse-Glehen ◽  
Aurelie Verney ◽  
Lucille Baseggio ◽  
Pascale Felman ◽  
Evelyne Callet-Bauchu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Mutations ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Marginal Zone B Cells ◽  
Mutational Status ◽  
Frequent Absence

Abstract Background and Objectives Splenic and nodal marginal zone B cell lymphoma (SMZL and NMZL) have been recently identified as distinct clinicopathological entities in the WHO classification. These lymphomas entities may have a common origin in the marginal B-cell compartment of the lymphoid organs. However the precise cell of origin of marginal zone B cells, its status in the B cell differentiation pathway and the mechanisms involved in lymphomagenesis remain unclear. The most widely held view is that marginal zone B cells are mostly memory B cells. But the origin of these cells, especially the transit through germinal center pathway, remains contradictory. Somatically mutated variable-region of immunoglobulin genes and bcl-6 gene represent at this time faithful markers for exposure to the germinal center. In addition, aberrant somatic hypermutations have been suggested to contribute to the development of B-cell lymphomas, occurring in the 5′ sequence of several proto-oncogenes. Interestingly those mutation do not occur in normal germinal center B cells. Design and Methods: IgVH, BCL-6, PIM1, Rho/TTF and PAX 5 genes, highly mutated in DLBCL and other indolent lymphoma such as B-CLL, were analysed for the presence of somatic mutations from 50 marginal zone lymphoma tissue and blood samples (21 NMZL and 29 SMZL including 10 cases with numerous villous lymphoma cells in peripheral blood). According to the morphological and immunophenotypical analysis, the fraction of malignant cells in the specimen was 70% or more in all cases. Mutational analysis was restricted to the regions previously shown to contain more than 95% of mutations in DLBCL. PCR products were directly sequenced on both sides and perfomed in duplicate in two independent reactions. Results: Out of 18 NMZL cases analysed for IgVH mutational status (3 cases not analysed for IgVH) 15 cases were mutated and 21 out of 28 in SMZL cases. Mutation of BCL-6 was detected in only 1 NMZL patients (1/21) and 1 SMZL patients (1/29). For RhoH/TTF, PIM1, PAX5 the mutation average was also low with only 1 case mutated per group and per gene, with a different case mutated in each for each gene. Conclusion In summary, we demonstrate the low frequency of aberrant somatic mutations in SMZL and NMZL, suggesting that this process is probably not a major contributor to lymphomageneis. However the frequent absence of mutation in BCL6 suggest a particular differentiation pathway, as suggested before in normal marginal zone B cells, possibly without transit through the germinal center. Interestingly the relatively high frequency of VH mutated cases compared with the frequent absence of mutation of BCL6, considered as a specific germinal center tag, could suggest somatic hypermutation outside the germinal center. In addition the absence of hypermutation could be linked with the absence of recurrent translocation in SMZL and NMZL, the translocation process haveing been associated with somatic hypermutation dysfunction.

scholarly journals Somatic hypermutation and B–cell lymphoma

2001 ◽  
Vol 356 (1405) ◽  
pp. 73-82 ◽  
Author(s):  
Deborah Dunn–Walters ◽  
Christian Thiede ◽  
Birgit Alpen ◽  
Jo Spencer
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Response Analysis ◽  
Lymphoid Tissues ◽  
Sequence Information ◽  
Marginal Zone B Cells

During the B–cell response to T–cell–dependent antigens, the B cells undergo a rapid proliferative phase in the germinal centre. This is accompanied by the introduction of mutations into the immunoglobulin (Ig) variable region (V) genes. The B cells are then selected according to the affinity of the encoded immunoglobulin for antigen, resulting in affinity maturation of the response. Analysis of mutations in IgV genes has given insight into the history of individual B cells and their malignancies. In most cases, analysis of mutations confirms classifications of B–cell lineage designated by studies of cellular morphology and surface antigen expression. However, of particular interest is the subdivision of groups of malignancies by analysis of somatic hypermutation. It is now apparent that there are two subsets of chronic lymphocytic leukaemia (CLL), one with a low load of mutations and poor prognosis, and one with a heavy load of mutations with a much more favourable prognosis. In addition, in Burkitt's lymphoma, sporadic and endemic subtypes are now considered possibly to have a different pathogenesis, reflected in differences in the numbers of mutations. Hodgkin's disease, which was a mystery for many years, has now been shown to be a B–cell tumour. Although in many cases the Ig genes are crippled by somatic hypermutation, it is thought that failure to express Ig is more likely to be associated with problems of transcription. It has been proposed that the distribution of mutations in a B–cell lymphoma can be used to determine whether a lymphoma is selected. We have investigated the load and distribution of mutations in one group of lymphomas–marginal zone B–cell lymphomas of mucosa–associated lymphoid tissues (MALT–type lymphoma), which are dependent on Helicobacter pylori for disease progression, to investigate the limits of information that can be derived from such studies. Comparison of the load of mutations demonstrates that these tumours have approximately the same load of mutations as normal mucosal marginal zone B cells from the Peyer's patches and mucosal plasma cells. This is consistent with the origin of these cells from mucosal marginal zone B cells with plasma cell differentiation. To investigate selection in MALT lymphomas we compared a region of the framework region three in ten MALT lymphomas which use the V H4 family, with the same codons in groups of V H4 genes that are out of frame between V and J. The latter accumulate mutations but are not used and are not selected. A group of V H4 genes are in–frame between V and J were also included for comparison. There were no obvious differences in the distribution of mutations between the groups of genes; the same hot spots and cold spots were apparent in each. In the MALT lymphomas, selection was apparent in the framework regions only and the tendency was to conserve. We therefore feel that there is selection to conserve antibody structure and that this does not reflect selection for antigen. We do not believe that antigen selection can be deduced reliably from sequence information alone. It is possible that somatic hypermutation could be a cause of malignancy since it has been shown that the process may generate DNA strand breaks and is known to be able to generate insertions and deletions. Such events may mediate the translocation of genes—a process that is pivotal in the evolution of many lymphomas.

Ligation of tumour-produced mucins to CD22 dramatically impairs splenic marginal zone B-cells

2009 ◽  
Vol 417 (3) ◽  
pp. 673-683 ◽  
Author(s):  
Munetoyo Toda ◽  
Risa Hisano ◽  
Hajime Yurugi ◽  
Kaoru Akita ◽  
Kouji Maruyama ◽  
...  
Keyword(s):  
Sialic Acid ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Signalling ◽  
Negative Regulator ◽  
Mammary Adenocarcinoma ◽  
Marginal Zone B Cells ◽  
Tumour Bearing

CD22 [Siglec-2 (sialic acid-binding, immunoglobulin-like lectin-2)], a negative regulator of B-cell signalling, binds to α2,6- sialic acid-linked glycoconjugates, including a sialyl-Tn antigen that is one of the typical tumour-associated carbohydrate antigens expressed on various mucins. Many epithelial tumours secrete mucins into tissues and/or the bloodstream. Mouse mammary adenocarcinoma cells, TA3-Ha, produce a mucin named epiglycanin, but a subline of them, TA3-St, does not. Epiglycanin binds to CD22 and inhibits B-cell signalling in vitro. The in vivo effect of mucins in the tumour-bearing state was investigated using these cell lines. It should be noted that splenic MZ (marginal zone) B-cells were dramatically reduced in the mice bearing TA3-Ha cells but not in those bearing TA3-St cells, this being consistent with the finding that the thymus-independent response was reduced in these mice. When the mucins were administered to normal mice, a portion of them was detected in the splenic MZ associated with the MZ B-cells. Furthermore, administration of mucins to normal mice clearly reduced the splenic MZ B-cells, similar to tumour-bearing mice. These results indicate that mucins in the bloodstream interacted with CD22, which led to impairment of the splenic MZ B-cells in the tumour-bearing state.

scholarly journals Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Cristina de Vera Mudry ◽  
Franziska Regenass-Lechner ◽  
Laurence Ozmen ◽  
Bernd Altmann ◽  
Matthias Festag ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Nuclear Translocation ◽  
Recovery Period ◽  
Functional Characterization ◽  
Notch Receptor ◽  
Marginal Zone B Cells ◽  
Cell Fate Decisions

Theγ-secretase complex is a promising target in Alzheimer’s disease because of its role in the amyloidogenic processing ofβ-amyloid precursor protein. This enzyme also catalyzes the cleavage of Notch receptor, resulting in the nuclear translocation of intracellular Notch where it modulates gene transcription. Notch signaling is essential in cell fate decisions during embryogenesis, neuronal differentiation, hematopoiesis, and development of T and B cells, including splenic marginal zone (MZ) B cells. This B cell compartment participates in the early phases of the immune response to blood-borne bacteria and viruses. Chronic treatment with the oralγ-secretase inhibitor RO4929097 resulted in dose-dependent decreased cellularity (atrophy) of the MZ of rats and mice. Significant decreases in relative MZ B-cell numbers of RO4929097-treated animals were confirmed by flow cytometry. Numbers of MZ B cells reverted to normal after a sufficient RO4929097-free recovery period. Functional characterization of the immune response in relation to RO4929097-related MZ B cell decrease was assessed in mice vaccinated with inactivated vesicular stomatitis virus (VSV). Compared with the immunosuppressant cyclosporin A, RO4929097 caused only mild and reversible delayed early neutralizing IgM and IgG responses to VSV. Thus, the functional consequence of MZ B cell decrease on host defense is comparatively mild.

Vav proteins regulate peripheral B-cell survival

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2391-2398 ◽  
Author(s):  
Elena Vigorito ◽  
Laure Gambardella ◽  
Francesco Colucci ◽  
Simon McAdam ◽  
Martin Turner
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Cross Linking ◽  
Marginal Zone B Cells ◽  
Survival Signal ◽  
B Cell Survival ◽  
Follicular B Cells ◽  
Deficient Mice

AbstractMice lacking all 3 Vav proteins fail to produce significant numbers of recirculating follicular or marginal zone B cells. Those B cells that do mature have shortened lifespans. The constitutive nuclear factor-kappaB (NF-κB) activity of resting naive B cells required Vav function and expression of cellular reticuloendotheliosis (c-Rel). Rel-A was reduced in Vav-deficient B cells. Furthermore, expression of the NF-κB-regulated antiapoptotic genes A1 and Bcl-2 was reduced in mature Vav-deficient B cells. Overexpression of Bcl-2 restored the number of mature follicular B cells in the spleens of Vav-deficient mice. When activated by B-cell receptor (BCR) cross-linking, Vav-deficient B cells failed to activate NF-κB. Vav proteins thus regulate an NF-κB-dependent survival signal in naive B cells and are required for NF-κB function after BCR cross-linking.

Marginal Zone B Cells Mediate a CD4 T Cell Dependent Extrafollicular Antibody Response Following RBC Transfusion in Mice

Blood ◽  
2021 ◽  
Author(s):  
Patricia E Zerra ◽  
Seema R Patel ◽  
Ryan Philip Jajosky ◽  
Connie M Arthur ◽  
James W McCoy ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
T Cell Activation ◽  
Antibody Formation ◽  
Marginal Zone ◽  
Cd4 T Cell ◽  
Marginal Zone B Cells ◽  
Rbc Transfusion

Red blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme and ovalbumin fused to human Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they co-localize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited IgM and IgG anti-HOD antibody formation, while CD4 T cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild type or MZ B cell deficient recipients, suggesting that IgG formation is not dependent on MZ B cell-mediated CD4 T cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response and no increase in antigen specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.

scholarly journals NR4A Expression by Human Marginal Zone B-Cells

Antibodies ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 50
Author(s):  
Kim Doyon-Laliberté ◽  
Josiane Chagnon-Choquet ◽  
Michelle Byrns ◽  
Matheus Aranguren ◽  
Meriam Memmi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Population ◽  
Human Blood ◽  
Marginal Zone ◽  
Ex Vivo ◽  
Transcriptome Profiling ◽  
Marginal Zone B Cells ◽  
Healthy Donors ◽  
And Function

We have previously characterized a human blood CD19+CD1c+IgM+CD27+CD21loCD10+ innate-like B-cell population, which presents features shared by both transitional immature and marginal zone (MZ) B-cells, named herein “precursor-like” MZ B-cells. B-cells with similar attributes have been associated with regulatory potential (Breg). In order to clarify this issue and better characterize this population, we have proceeded to RNA-Seq transcriptome profiling of mature MZ and precursor-like MZ B-cells taken from the blood of healthy donors. We report that ex vivo mature MZ and precursor-like MZ B-cells express transcripts for the immunoregulatory marker CD83 and nuclear receptors NR4A1, 2, and 3, known to be associated with T-cell regulatory (Treg) maintenance and function. Breg associated markers such as CD39 and CD73 were also expressed by both populations. We also show that human blood and tonsillar precursor-like MZ B-cells were the main B-cell population to express elevated levels of CD83 and NR4A1-3 proteins ex vivo and without stimulation. Sorted tonsillar precursor-like MZ B-cells exerted regulatory activity on autologous activated CD4+ T-cells, and this was affected by a CD83 blocking reagent. We believe these observations shed light on the Breg potential of MZ populations, and identify NR4A1-3 as potential Breg markers, which as for Tregs, may be involved in stabilization of a regulatory status. Since expression and activity of these molecules can be modulated therapeutically, our findings may be useful in strategies aiming at modulation of Breg responses.

B Cells with BCL2/IGH Translocation Compose a Distinctive Cell Population That May Serve as a Reservoir of Lymphoma of Germinal Center B-Cell Type.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2050-2050
Author(s):  
Tomomi Sakai ◽  
Momoko Nishikori ◽  
Masaharu Tashima ◽  
Ryo Yamamoto ◽  
Toshio Kitawaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Marginal Zone ◽  
Terminal Differentiation ◽  
Follicular Dendritic Cells ◽  
Marginal Zone B Cells ◽  
Germinal Center B Cell ◽  
Follicular B Cells

Abstract BCL2/IGH translocation is a hallmark of follicular lymphoma and diffuse large B-cell lymphoma of germinal center B-cell type. Although being a strong determinant of these histological subtypes, this translocation is considered to be insufficient by itself and further gene alterations are necessary for cellular transformation. In Eμ-BCL2 transgenic (Tg) mice, B-lineage cells are increased by several-fold compared to wild-type (WT) mice, but only 5–15 % of them develop disease in the first year of life. To clarify how the BCL2 translocation contributes to the development of specific lymphoma subtypes, we created two types of chimeric mouse models to characterize the biological features of BCL2-overexpressing B cells in normal individuals. First, we introduced CD19 promoter-driven BCL2 and its mutant genes to a minor population of murine bone marrow cells by using a lentiviral vector system and transplanted into irradiated mice. BCL2-overexpressing B cells showed increased follicular and reduced marginal zone populations. The same phenotypic shift was observed in B cells introducing BCL2-Y28F mutant that retained anti-apoptotic function, but a defective mutant BCL2-G142A and a mock vector did not affect B-cell phenotype. Additionally, BCL2-introduced B cells showed decreased cell size compared to those introduced BCL2-G142A and mock vectors. To assess the functional alteration of BCL2-overexpressing B cells, TNP-Ficoll binding experiment was performed. The result showed diminished T-cell independent response in parallel with decreased marginal zone B cells. The low transformation frequency of B cells in Eμ-BCL2 Tg mice has been partly explained by their propensity to reside in the G0 phase of the cell cycle (reviewed in Oncogene, 18:5268,1999). We hypothesized that the microenvironment of B cells in Eμ-BCL2 Tg mice might be altered by abnormal B cells themselves. To evaluate the influence of the different microenvironments on BCL2-overexpressing B cells, we next made Eμ-BCL2/CAG-GFP double Tg mice and transferred their bone marrow mononuclear cells into WT or Eμ-BCL2 Tg mice. Blastic cell population of BCL2+GFP+ B cells was larger in those transferred to WT mice compared to those transferred to Eμ-BCL2 Tg mice, regardless of the same phenotypic preference toward follicular B cells. BrdU uptake experiments demonstrated continuous cell cycle progression of the BCL2+GFP+ B cells in WT mice but repressed cell cycle of those in Eμ-BCL2 Tg mice. In immunohistochemical analysis, splenic follicles were disorganized with reduced follicular dendritic cells and inadequate T cell accumulation in Eμ-BCL2 Tg mice. Functional impairment of splenic follicles in Eμ-BCL2 Tg mice might be caused by decreased marginal zone B cell subset, as the antigen capture and delivery by marginal zone B cells was reported to play an important role in the development of follicular dendritic cells. To understand the fate of BCL2-overexpressing B cells after stimulation, we finally assessed their terminal differentiation capacity in vitro. Plasma cell differentiation was suppressed in B cells derived from Eμ-BCL2 Tg mice under either LPS or anti-IgM antibody stimulation. BCL2 is reported to impede the activity of transcription factor NF-AT (Proc Natl Acad Sci93:9545,1996; Nature386:728,1997), and we found that calcineurin inhibitor FK506 suppressed plasma cell differentiation of WT B cells. Gene regulation patterns of the Eμ-BCL2+ B cells were similar to B cells stimulated in the presence of FK506 as well, suggesting that repressed terminal differentiation in Eμ-BCL2+ B cells was partly caused by the suppressed activity of NF-AT. In summary, BCL2-deregulated B cells preferentially differentiate into follicular B cells, and as a result of decreased terminal differentiation in addition to their anti-apoptotic property, they may be obliged to survive and recirculate as memory B cells, and accumulate genetic abnormalities while they repeatedly pass through the germinal center. As the germinal center is the particular site where they can counterbalance the cell cycle-retarding effect of BCL2, it may be a specific place for generating lymphoma triggered by BCL2/IGH translocation. Our results emphasize the importance of the microenvironment of pre-malignant cells during transformation process, and suggest that a simple transgenic mouse model may not be always appropriate for the study of oncogenesis.

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