**1. Germinal center B-cell dynamics**

Characteristic chromosome translocation is associated with certain entities of the disease that is known to play a key role in the development of lymphoma. Chromosomal translocation alone, however, is not sufficient for the appearance of a tumor. Various factors, including microenvironment, epigenetic, and genetic changes, play a role in the development of lymphomas. Follicular dendritic cells (FDC) produce high-affinity antibody needed for the development of B-cell memory. These cells can be detected in B-cell non-Hodgkin lymphomas (NHL). Gene-expression profiling revealed that the FDC network could affect the clinical outcome in DLBCL [1–3].

Transgenic mouse model with different genes linked to chromosomal translocations has shown that chromosomal translocation alone is not sufficient for the development of lymphoma [1]. Transgenic mice with the c-*MYC* (myelomatosis viral oncogene homolog) genome develop lymphoma after a long time. The *c-MYC* gene is located at 8q24 and is associated with the translocation t (8; 14) (q24; q32). This was the first recurring chromosome abnormality ever reported in lymphoproliferative disorders. *C-MYC* in place next to immunoglobulin heavy locus (IGH) results in the expression of c-Myc protein, which is a key transcriptional factor that promotes cell cycle and

tumor proliferation. 8q24/*c-MYC* restenosis is found in 7–15% of the activated B-celllike (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL), and the reports are predominantly associated with extranodal localization [4–8]. B-cell lymphomas include follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Tumor cells show a strict topographical and functional relationship with FDCs, included with reactive lymphoid and stromal cells [3, 9]. The FDC patterns, described for FL and MCL, are reminiscent of the distribution pattern of FCD meshwork seen in the GC or the mantle zone of the secondary lymphoid follicle, respectively [3, 9]. T cells migrate to B-cell-enriched follicles and germinal centers within secondary lymphoid organs to provide help to B cells. Correlation T and B cells within germinal centers are essential for B-cell differentiation into germinal center B cells and selection of mutated cells into memory B cells or memory plasma cells. Different stages of maturation lead to B cell becoming a helper T cells and B follicular helper T (TFH) cells [10].

*C-MYC* translocation is characteristic of Burkitt's lymphoma, where it is found in 80–90% of cases. In B-cell lymphoma 2 (*BCL2*) transgenic mice, it has been shown that polyclonal B-cell proliferation causes the growth of lymphoid follicles, but only 20% of mice develop monoclonal diffuse lymphomas after long latency. Long-term exposure to oncogene, progression from polyclonal to monoclonal disease, and appearance of the *BCL2* transgenic mouse model suggests that lymphoma development depends on the secondary genetic events [8].

*C-MYC* is a strong transcription factor and promotes cell proliferation and growth, DNA replication, and protein biosynthesis [11]. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas but is rarely reported in T-cell lymphomas. *C*-*MYC* rearrangement is found in multiple B-cell lymphomas including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and B-cell lymphoma unclassifiable, with features intermedia between DLBCL and Burkitt lymphoma (BCLU). In normal cells *c-MYC* is a highly regulated transcription factor that is involved in cell cycle regulation, cell metabolism, mitochondrial biogenesis, nucleic acid synthesis, and apoptosis [12]. *C-MYC* expression is detected in a much higher proportion of DLBCL (30–50%) and is associated with concomitant expression of *BCL2* in 20 to 35% of cases [8]. Most of these tumors do not carry *c-MYC/BCL2* chromosomal alterations and have been named "double-hit lymphoma." Most studies use a cutoff of 40% *c-MYC*-expressing cells to define these cases; the cutoff for *BCL2* expression has varied considerably in the literature, but a figure of 50% is recommended [8, 13–16].

Germinal centers (GCs) form in the center of the B-cell follicles of secondary lymphoid organs, interspersed within a network of stromal cells known as follicular dendritic cells (FDCs) [17, 18]. In follicles that do not contain GCs (primary follicles), FDCs play an important role, helping B cells to cluster into compact, well-defined follicle [18–20]. FDC has a long-term retention of antigen within complement immune complexes in a form that can support affinity-dependent "testing" of immunoglobulin somatic hypermutation (SHM)-modified B-cell Ag receptors (BCRs) that occurs during GC selection [21, 22]. Adaptive immunity involves the development of antibodies in GCs through SHM in GC dark zones (DZs) and clonal selection in light zones (LZs) [22, 23].

The spleen, lymph nodes, and mucosal-associated lymphoid tissues constitute secondary lymphoid tissues that are located strategically to efficiently trap foreign antigens entering peripheral tissues and mucosal sites. In secondary lymphoid tissues, activation of B cells and T cells by native and processed antigenic determinants represents the beginning of the GC reaction [24]. The B cells bind membrane-bound immunoglobulins (B-cell receptors (BCR)) and express Ag-derived peptides in major histocompatibility complex (MHC-II) molecules on their surface [6]. Secondary lymphoid tissues facilitate interactions between antigen-bearing dendritic cells (DCs), B cells, and T cells to initiate adaptive immune responses. B cells express

**77**

*B Cell Lymphomagenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.87241*

B-cell receptors (BCRs) on their cell membrane, and BCRs allow the cell to bind to a specific antigen and initiate an antibody response [18, 23, 25]. Despite these common features, differences in routes of antigen transport, lymphocyte trafficking, and unique cell populations determine the role of a specific secondary lymphoid tissue in immune responses to various foreign antigens. In the GCs, naive B cells can have

Germinal centers (GCs) are organized into two major zones: dark and light zones. The dark zone contains large centroblasts that are rapidly proliferating and undergoing somatic mutation. These cells grow to small nonproliferating centrocytes in the light zone, and binding antigen on follicular dendritic cells (FDCs) and development further depend on receiving signals from helper T cells [18, 22, 23, 28]. The activated B cells have two possibilities: (1) turnover into extrafollicular areas followed by proliferation and terminal differentiation into short-lived plasma cells that secrete antibody and (2) turnover into B-cell follicles followed by proliferation of GCs [27]. The mechanisms responsible for this remain poorly understood, although various studies suggest that the affinity of the BCR for the foreign antigen, the amount of antigen-receptor engagement, and the costimulatory signals received

from T cells may all be involved. These observations suggest that the affinity maturation of the antibody response occurs in GCs, through the processes of clonal

T cells play a key role to induce B-cell proliferation and somatic hypermutation and to limit GC reactions. T cells in the germinal center activate helper T cells (CD4+CD57+CD25−) migrating in the germinal center to activate the B-cell zone-homing C-X-C chemokine receptor type 5 (CXCR5) [29, 30]. B cells primarily excrete interleukin 4 (IL-4). They begin in the paracortical T-cell area of IgD follicle expression, but T-cell maturation results in a characteristic follicular CD10+ immunophenotype that has been acquired. Although the germinal center formation is intact in the presence of the FDC network, FDC plays a key role in the formation of memory B cell, and interaction is dependent on the expression of the tumor necrosis factor (TNF) family. The germinal center is not only created from different stages of B-cell maturation but also through the division of immunophenotypically different and functionally specialized T cells, dendritic cells, and subpopulations of stromal cells and their interactions. The antigen-stimulated B cells with the germinal center are highly mobile within the zone as well as between the dark and light zone [18, 23, 31]. In general, naive B cells in the central lymphatic system mature through the transformation and proliferation of B cells toward plasma cells and B cells that produce antibodies. Malignant diseases may develop during such processes, and B-cellular neoplasms tend to imitate different stages of normal B-cell differentiation [1]. In the primary phase of differentiation, the progenitor of the B cell passes through renaming, and further development is followed by immunoglobulin genes (Ig) and occurs at naive B cells in peripheral lymphoid tissue or passes through apoptosis. Naive B cells can enter the primary follicle, forming a germinal center (GC), where mature CD10- and B-cell lymphoma 6 (*BCL6)* centroblasts expression mature [2]. Centroblasts continue maturing in centrocytes, which later co-express *BCL2 gene*. Naive B cells can be directly developed in plasma cells. The germinal center is partially monitored by Bcl6 protein, which in humans is encoded by the *BCL6* [32] and IRF4/MUM1 proteins, which is essential for further lymphocyte differentiation into plasma cells or memory B cell. On the other hand, antigen stimulation of lymphocyte can go toward apoptosis [2]. MUM1 is a lymphocyte-specific transcriptional factor of the interferon regulatory factor (IRF) family, included in the regulation of gene expression in response to interferon and other cytokines. MUM1 provides immunoglobulin gene expression in the final step of B-cell differentiation within

proliferation, somatic hypermutation, and selection [27].

germinal center light zones. At this stage Bcl-6 is downregulated [2].

clonal expansion, somatic hypermutation, and maturation [26, 27].

#### *B Cell Lymphomagenesis DOI: http://dx.doi.org/10.5772/intechopen.87241*

*Normal and Malignant B-Cell*

tumor proliferation. 8q24/*c-MYC* restenosis is found in 7–15% of the activated B-celllike (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL), and the reports are predominantly associated with extranodal localization [4–8]. B-cell lymphomas include follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Tumor cells show a strict topographical and functional relationship with FDCs, included with reactive lymphoid and stromal cells [3, 9]. The FDC patterns, described for FL and MCL, are reminiscent of the distribution pattern of FCD meshwork seen in the GC or the mantle zone of the secondary lymphoid follicle, respectively [3, 9]. T cells migrate to B-cell-enriched follicles and germinal centers within secondary lymphoid organs to provide help to B cells. Correlation T and B cells within germinal centers are essential for B-cell differentiation into germinal center B cells and selection of mutated cells into memory B cells or memory plasma cells. Different stages of maturation lead to B cell becoming a helper T cells and B follicular helper T (TFH) cells [10]. *C-MYC* translocation is characteristic of Burkitt's lymphoma, where it is found in 80–90% of cases. In B-cell lymphoma 2 (*BCL2*) transgenic mice, it has been shown that polyclonal B-cell proliferation causes the growth of lymphoid follicles, but only 20% of mice develop monoclonal diffuse lymphomas after long latency. Long-term exposure to oncogene, progression from polyclonal to monoclonal disease, and appearance of the *BCL2* transgenic mouse model suggests that lymphoma

*C-MYC* is a strong transcription factor and promotes cell proliferation and growth, DNA replication, and protein biosynthesis [11]. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas but is rarely reported in T-cell lymphomas. *C*-*MYC* rearrangement is found in multiple B-cell lymphomas including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and B-cell lymphoma unclassifiable, with features intermedia between DLBCL and Burkitt lymphoma (BCLU). In normal cells *c-MYC* is a highly regulated transcription factor that is involved in cell cycle regulation, cell metabolism, mitochondrial biogenesis, nucleic acid synthesis, and apoptosis [12]. *C-MYC* expression is detected in a much higher proportion of DLBCL (30–50%) and is associated with concomitant expression of *BCL2* in 20 to 35% of cases [8]. Most of these tumors do not carry *c-MYC/BCL2* chromosomal alterations and have been named "double-hit lymphoma." Most studies use a cutoff of 40% *c-MYC*-expressing cells to define these cases; the cutoff for *BCL2* expression has varied

considerably in the literature, but a figure of 50% is recommended [8, 13–16].

(DZs) and clonal selection in light zones (LZs) [22, 23].

Germinal centers (GCs) form in the center of the B-cell follicles of secondary lymphoid organs, interspersed within a network of stromal cells known as follicular dendritic cells (FDCs) [17, 18]. In follicles that do not contain GCs (primary follicles), FDCs play an important role, helping B cells to cluster into compact, well-defined follicle [18–20]. FDC has a long-term retention of antigen within complement immune complexes in a form that can support affinity-dependent "testing" of immunoglobulin somatic hypermutation (SHM)-modified B-cell Ag receptors (BCRs) that occurs during GC selection [21, 22]. Adaptive immunity involves the development of antibodies in GCs through SHM in GC dark zones

The spleen, lymph nodes, and mucosal-associated lymphoid tissues constitute secondary lymphoid tissues that are located strategically to efficiently trap foreign antigens entering peripheral tissues and mucosal sites. In secondary lymphoid tissues, activation of B cells and T cells by native and processed antigenic determinants represents the beginning of the GC reaction [24]. The B cells bind membrane-bound

immunoglobulins (B-cell receptors (BCR)) and express Ag-derived peptides in major histocompatibility complex (MHC-II) molecules on their surface [6]. Secondary lymphoid tissues facilitate interactions between antigen-bearing dendritic cells (DCs), B cells, and T cells to initiate adaptive immune responses. B cells express

development depends on the secondary genetic events [8].

**76**

B-cell receptors (BCRs) on their cell membrane, and BCRs allow the cell to bind to a specific antigen and initiate an antibody response [18, 23, 25]. Despite these common features, differences in routes of antigen transport, lymphocyte trafficking, and unique cell populations determine the role of a specific secondary lymphoid tissue in immune responses to various foreign antigens. In the GCs, naive B cells can have clonal expansion, somatic hypermutation, and maturation [26, 27].

Germinal centers (GCs) are organized into two major zones: dark and light zones. The dark zone contains large centroblasts that are rapidly proliferating and undergoing somatic mutation. These cells grow to small nonproliferating centrocytes in the light zone, and binding antigen on follicular dendritic cells (FDCs) and development further depend on receiving signals from helper T cells [18, 22, 23, 28].

The activated B cells have two possibilities: (1) turnover into extrafollicular areas followed by proliferation and terminal differentiation into short-lived plasma cells that secrete antibody and (2) turnover into B-cell follicles followed by proliferation of GCs [27]. The mechanisms responsible for this remain poorly understood, although various studies suggest that the affinity of the BCR for the foreign antigen, the amount of antigen-receptor engagement, and the costimulatory signals received from T cells may all be involved. These observations suggest that the affinity maturation of the antibody response occurs in GCs, through the processes of clonal proliferation, somatic hypermutation, and selection [27].

T cells play a key role to induce B-cell proliferation and somatic hypermutation and to limit GC reactions. T cells in the germinal center activate helper T cells (CD4+CD57+CD25−) migrating in the germinal center to activate the B-cell zone-homing C-X-C chemokine receptor type 5 (CXCR5) [29, 30]. B cells primarily excrete interleukin 4 (IL-4). They begin in the paracortical T-cell area of IgD follicle expression, but T-cell maturation results in a characteristic follicular CD10+ immunophenotype that has been acquired. Although the germinal center formation is intact in the presence of the FDC network, FDC plays a key role in the formation of memory B cell, and interaction is dependent on the expression of the tumor necrosis factor (TNF) family. The germinal center is not only created from different stages of B-cell maturation but also through the division of immunophenotypically different and functionally specialized T cells, dendritic cells, and subpopulations of stromal cells and their interactions. The antigen-stimulated B cells with the germinal center are highly mobile within the zone as well as between the dark and light zone [18, 23, 31].

In general, naive B cells in the central lymphatic system mature through the transformation and proliferation of B cells toward plasma cells and B cells that produce antibodies. Malignant diseases may develop during such processes, and B-cellular neoplasms tend to imitate different stages of normal B-cell differentiation [1].

In the primary phase of differentiation, the progenitor of the B cell passes through renaming, and further development is followed by immunoglobulin genes (Ig) and occurs at naive B cells in peripheral lymphoid tissue or passes through apoptosis. Naive B cells can enter the primary follicle, forming a germinal center (GC), where mature CD10- and B-cell lymphoma 6 (*BCL6)* centroblasts expression mature [2]. Centroblasts continue maturing in centrocytes, which later co-express *BCL2 gene*. Naive B cells can be directly developed in plasma cells. The germinal center is partially monitored by Bcl6 protein, which in humans is encoded by the *BCL6* [32] and IRF4/MUM1 proteins, which is essential for further lymphocyte differentiation into plasma cells or memory B cell. On the other hand, antigen stimulation of lymphocyte can go toward apoptosis [2]. MUM1 is a lymphocyte-specific transcriptional factor of the interferon regulatory factor (IRF) family, included in the regulation of gene expression in response to interferon and other cytokines. MUM1 provides immunoglobulin gene expression in the final step of B-cell differentiation within germinal center light zones. At this stage Bcl-6 is downregulated [2].

Secondary follicles are important for B-cell differentiation and maturation. B-cell differentiation begins via gene resection for the DJ region of the IgH gene. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. This region represents the organization of heavy-chain locus. The locus includes variable (V), diversity (D), joining (J), and constant (C) segments. Within B-cell development, DNA recombination level joins a single D segment with a J segment; the fused DJ segment of a DNA molecule containing information coding for a protein or peptide sequence of this partially rearranged DJ region is then joined to the V segment. The introduction of region V into DJ results in VDJ coupling, and then the conversion successfully generates IGH protein chain. After the successful generation of the IgH gene, Ig light chains (IgL) are formed. The removal of IgL starts with light chain kappa. When the IgH and IgL genes are productive, B cells are called naive B cells because they are not exposed to the appropriate antigens and reside in the marginal zone of the secondary follicle [4]. The cells that have not been exposed to antigens are known as naïve or virgin B cells and remain at the mantle zone until they are exposed to antigens [22]. According to the B-cell differentiation stage, B-cell precursor includes B lymphoblastic leukemia/lymphoma, while pre-GC neoplasms include cell lymphoma. GC B-cell tumors are follicular lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, and diffuse large B-cell lymphoma (DLBCL). In the last stage of B-cell differentiation, post-GC neoplasms, including marginal zone lymphoma, mucosa-associated lymphoma tissue (MALT), lymphoplasmic lymphoma, chronic lymphocytic leukemia (CLL), plasma cell myeloma, and some cases of DLBCL, are developed [1, 22] (**Figure 1**).

The majority of B-cell lymphomas appear from germinal center (GC) B cells, but it is unclear to what extent B cells in lymphoma keep the functional dynamics of GC B cells or are blocked at a special stage of the GC reaction [20].

The germinal center is probably the source of many lymphomas. The germinal center reaction begins when antigens, with T-cell signals, activate centroblasts that migrate from the dark zone to the light zone and begin to express their antibodies

**79**

*B Cell Lymphomagenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.87241*

B cell activation and the GC response [18, 20, 23].

tion takes place in favor of plasma cells [25, 39].

CD5 is a transmembrane glycoprotein with expression on the surface of T cells and a subset of B cells. The absence of CD5 performs thymocytes hyperresponsive to stimulation through the T-cell antigen receptor (TCR) in vitro. CD5 can influence the developing thymocytes by acting as a negative regulator of TCR-mediated signal transduction [34]. The CD5 signature included downregulated extracellular matrix genes such as *POSTN*, *SPARC*, *COL1A1*, *COL3A1*, *CTSK*, *MMP9*, and *LAMB3* and

Bcl6 protein suppresses many genes involved in plasma cell differentiation, cell cycle progression, and responses to DNA damage and cell death. One of these genes is the transcription factor Blimp-1, the main regulator of plasma cell differentiation that reduces gene expression of mature B cells. The transcription factors Blimp-1 and IRF4 are essential for plasma cell generation. However, their function in mature plasma cells has remained elusive. B cells germinate center begins to differentiate plasma cells, monitored by interferon regulatory factor 4 (IRF4)/MUM1, whose transcription factor is needed for conversion to plasma cells. IRF4 increases the expression of Blimp-1 [39], and this growth is suppressed by *BCL6*, so differentia-

The transcriptional repressor Blimp-1 originally cloned as a silencer of type I interferon (IFN)-β gene expression controls cell fate decisions in multiple tissue contexts. Blimp-1 functional loss in 3D cultures of mammary epithelial cells (MECs) results in

Chromosomal translocation in B-cell neoplasms is divided into three functional categories: proliferation, inhibition of differentiation, and antiapoptotic activity. These three categories are essential for understanding the mechanism of lymphomagenesis. For DLBCL with *BCL6* gene translocation, Bcl6 protein expression is a side for post-GC staging cells, but it is not yet clear what signal is needed. It is clear that the antiapoptotic function must be present for *BCL2*, which is expressed at the post-GC

the accumulation of dsRNA and expression of type III IFN-λ [39] (**Figure 3**).

comprised upregulated genes including *TRPM4* [35–38] (**Figure 2**).

on the cell surface known as centrocytes. Then apoptosis begins and competes for survival signals derived from FDCs and TFH cells. Germinal center selection is dependent on the tendency of their surface antibody to the antigen and can enter into the light zone of germinal centers, which are morphologically centrocytes and which are indivisible B cells with a notched core. The action or process of reentering into the dark zone as centroblasts gives a chance for nonselected B- cell mutants to gain more mutations in order to improve affinity toward antigen. Interactions with T cells are to prevent the generation of autoreactive germinal center B cells [18, 23, 33]. During the germinal center reaction, two different modifications of the B-cell DNA change B-cell receptor: somatic hypermutation and switch-off recombination. Both require activation-induced cytidine deaminase (AID). IgM, IgA, or IgE recurrence of IgM, IgG heavy-chain recombination changes occur, while somatic hypermutations imply mutations in the immunoglobulin-variable region, region that produces a population of B cells with an increase (or decrease) affinity for a particular antigen. These genetic modifications are essential for normal immune response but also a source of DNA damage that can become pathological with lymphoma [8]. Mature B-cell neoplasms involve about 30 different entities, while DLBCL is the most common type of non-Hodgkin's lymphoma (NHL), which accounts for about 40% of all non-Hodgkin's lymphomas (NHLs). B-cell lymphomas are identified by a combination of morphological features and recognizable immunophenotype [20]. A list of transcription factors that modulate the B-cell germinal center phenotype and where cell selectively express BCL6, and includes interferon-regulatory factor 4 (IRF4). IRF4 co-bound with the transcription factors PU.1 (plays a critical role in the development of white cells), and B-cell-activating transcription factor (BATF) to Ets or activator protein 1 (AP-1) composite motifs, united with genes involved in

**Figure 1.**

*B-cell differentiation and association of B-cell neoplasms [1].*

#### *B Cell Lymphomagenesis DOI: http://dx.doi.org/10.5772/intechopen.87241*

*Normal and Malignant B-Cell*

Secondary follicles are important for B-cell differentiation and maturation. B-cell differentiation begins via gene resection for the DJ region of the IgH gene. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. This region represents the organization of heavy-chain locus. The locus includes variable (V), diversity (D), joining (J), and constant (C) segments. Within B-cell development, DNA recombination level joins a single D segment with a J segment; the fused DJ segment of a DNA molecule containing information coding for a protein or peptide sequence of this partially rearranged DJ region is then joined to the V segment. The introduction of region V into DJ results in VDJ coupling, and then the conversion successfully generates IGH protein chain. After the successful generation of the IgH gene, Ig light chains (IgL) are formed. The removal of IgL starts with light chain kappa. When the IgH and IgL genes are productive, B cells are called naive B cells because they are not exposed to the appropriate antigens and reside in the marginal zone of the secondary follicle [4]. The cells that have not been exposed to antigens are known as naïve or virgin B cells and remain at the mantle zone until they are exposed to antigens [22]. According to the B-cell differentiation stage, B-cell precursor includes B lymphoblastic leukemia/lymphoma, while pre-GC neoplasms include cell lymphoma. GC B-cell tumors are follicular lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, and diffuse large B-cell lymphoma (DLBCL). In the last stage of B-cell differentiation, post-GC neoplasms, including marginal zone lymphoma, mucosa-associated lymphoma tissue (MALT), lymphoplasmic lymphoma, chronic lymphocytic leukemia (CLL), plasma cell

myeloma, and some cases of DLBCL, are developed [1, 22] (**Figure 1**).

GC B cells or are blocked at a special stage of the GC reaction [20].

The majority of B-cell lymphomas appear from germinal center (GC) B cells, but it is unclear to what extent B cells in lymphoma keep the functional dynamics of

The germinal center is probably the source of many lymphomas. The germinal center reaction begins when antigens, with T-cell signals, activate centroblasts that migrate from the dark zone to the light zone and begin to express their antibodies

**78**

**Figure 1.**

*B-cell differentiation and association of B-cell neoplasms [1].*

on the cell surface known as centrocytes. Then apoptosis begins and competes for survival signals derived from FDCs and TFH cells. Germinal center selection is dependent on the tendency of their surface antibody to the antigen and can enter into the light zone of germinal centers, which are morphologically centrocytes and which are indivisible B cells with a notched core. The action or process of reentering into the dark zone as centroblasts gives a chance for nonselected B- cell mutants to gain more mutations in order to improve affinity toward antigen. Interactions with T cells are to prevent the generation of autoreactive germinal center B cells [18, 23, 33].

During the germinal center reaction, two different modifications of the B-cell DNA change B-cell receptor: somatic hypermutation and switch-off recombination. Both require activation-induced cytidine deaminase (AID). IgM, IgA, or IgE recurrence of IgM, IgG heavy-chain recombination changes occur, while somatic hypermutations imply mutations in the immunoglobulin-variable region, region that produces a population of B cells with an increase (or decrease) affinity for a particular antigen. These genetic modifications are essential for normal immune response but also a source of DNA damage that can become pathological with lymphoma [8].

Mature B-cell neoplasms involve about 30 different entities, while DLBCL is the most common type of non-Hodgkin's lymphoma (NHL), which accounts for about 40% of all non-Hodgkin's lymphomas (NHLs). B-cell lymphomas are identified by a combination of morphological features and recognizable immunophenotype [20]. A list of transcription factors that modulate the B-cell germinal center phenotype and where cell selectively express BCL6, and includes interferon-regulatory factor 4 (IRF4). IRF4 co-bound with the transcription factors PU.1 (plays a critical role in the development of white cells), and B-cell-activating transcription factor (BATF) to Ets or activator protein 1 (AP-1) composite motifs, united with genes involved in B cell activation and the GC response [18, 20, 23].

CD5 is a transmembrane glycoprotein with expression on the surface of T cells and a subset of B cells. The absence of CD5 performs thymocytes hyperresponsive to stimulation through the T-cell antigen receptor (TCR) in vitro. CD5 can influence the developing thymocytes by acting as a negative regulator of TCR-mediated signal transduction [34]. The CD5 signature included downregulated extracellular matrix genes such as *POSTN*, *SPARC*, *COL1A1*, *COL3A1*, *CTSK*, *MMP9*, and *LAMB3* and comprised upregulated genes including *TRPM4* [35–38] (**Figure 2**).

Bcl6 protein suppresses many genes involved in plasma cell differentiation, cell cycle progression, and responses to DNA damage and cell death. One of these genes is the transcription factor Blimp-1, the main regulator of plasma cell differentiation that reduces gene expression of mature B cells. The transcription factors Blimp-1 and IRF4 are essential for plasma cell generation. However, their function in mature plasma cells has remained elusive. B cells germinate center begins to differentiate plasma cells, monitored by interferon regulatory factor 4 (IRF4)/MUM1, whose transcription factor is needed for conversion to plasma cells. IRF4 increases the expression of Blimp-1 [39], and this growth is suppressed by *BCL6*, so differentiation takes place in favor of plasma cells [25, 39].

The transcriptional repressor Blimp-1 originally cloned as a silencer of type I interferon (IFN)-β gene expression controls cell fate decisions in multiple tissue contexts. Blimp-1 functional loss in 3D cultures of mammary epithelial cells (MECs) results in the accumulation of dsRNA and expression of type III IFN-λ [39] (**Figure 3**).

Chromosomal translocation in B-cell neoplasms is divided into three functional categories: proliferation, inhibition of differentiation, and antiapoptotic activity. These three categories are essential for understanding the mechanism of lymphomagenesis. For DLBCL with *BCL6* gene translocation, Bcl6 protein expression is a side for post-GC staging cells, but it is not yet clear what signal is needed. It is clear that the antiapoptotic function must be present for *BCL2*, which is expressed at the post-GC

**Figure 2.**

*B-cellular differentiation and lymphomagenesis ([25], p. 1418).*

centers. There are indications that *BCL6* has the function of protecting cells from terminal differentiation and shows epigenetic changes that are conserved from human hematopoietic stem/progenitor cells (HSPCs) to mature B cells. These results suggest that *BCL6* may function in a "hit-and-run" role in lymphomagenesis [8].

Lymphomagenesis is a complex process that takes place in many steps, in which lymphocyte signal distortion, transcriptional regulation, and apoptosis lead to transformation. Experiments suggest that distorted expression of casein kinase II subunit alpha (CK2alpha) creates predispositions for lymphoma development. Further experiments suggest that CK2alpha lymphomas monitor the panel of lymphocyte transcription factors such as, for example, activator protein 1 (AP-1) and nuclear factor-kappaB (NF-ĸB) [40, 41]. NF-ĸB represents a group of related homodimeric and heterodimeric transcription factors that can activate different target genes involved in proliferation, differentiation, immune response, cell growth, and survival. Among the molecules induced by NF-ĸB are the cytokines, chemokines, and effectors of the immune response. NF-ĸB participates in response to inflammatory signals through T receptors, TNF receptors, and IL-1 receptors [40–42]. CREB is one of the best understood phosphorylation-dependent transcription factors (CREB) [16]. In effector T and B cells, immune receptor signals induce within minutes a rise of intracellular Ca++, the activation of the phosphatase calcineurin, and the

**81**

**Figure 3.**

*B Cell Lymphomagenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.87241*

translocation of NFAT transcription factors from cytosol to nucleus; the induction of NFATc1/αA takes place during the G1 phase of cell cycle [43, 44]. The NFAT signaling pathway oversees different aspects of cellular functions; NFAT has a function like calcium sensor, including calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates different cellular functions such as cell

TCF/LEFs are multifunctional proteins that use their sequence-specific DNAbinding and context-dependent interactions to specify which genes will be regulated by Wnts. The TCF/LEF families have been shown to regulate the expression of specific genes, such as c-Myc and Cyclin D1 [46]. These transcription factors are interdependent and closely linked with each other to form a network in the above signaling pathways, which regulate the entire process of osteoblast proliferation and differentiation [14]. Normally, these factors appear to be involved in the physiological activation response of lymphocytes before controlling the growth of malignant cells [47, 48].

Proliferation, differentiation, and apoptosis are associated with different types of lymphoma and chromosomal translocations. Each lymphoma has a separate proliferation of the site, which is most clearly described in the follicular lymphoma that proliferates in the follicle. Special chromosomal translocations are associated with

survival, proliferation, migration, invasion, and angiogenesis [44, 45].

*Oncogene path for three subtypes of DLBCL ([25], p. 1421).*

#### *B Cell Lymphomagenesis DOI: http://dx.doi.org/10.5772/intechopen.87241*

*Normal and Malignant B-Cell*

centers. There are indications that *BCL6* has the function of protecting cells from terminal differentiation and shows epigenetic changes that are conserved from human hematopoietic stem/progenitor cells (HSPCs) to mature B cells. These results suggest

Lymphomagenesis is a complex process that takes place in many steps, in which lymphocyte signal distortion, transcriptional regulation, and apoptosis lead to transformation. Experiments suggest that distorted expression of casein kinase II subunit alpha (CK2alpha) creates predispositions for lymphoma development. Further experiments suggest that CK2alpha lymphomas monitor the panel of lymphocyte transcription factors such as, for example, activator protein 1 (AP-1) and nuclear factor-kappaB (NF-ĸB) [40, 41]. NF-ĸB represents a group of related homodimeric and heterodimeric transcription factors that can activate different target genes involved in proliferation, differentiation, immune response, cell growth, and survival. Among the molecules induced by NF-ĸB are the cytokines, chemokines, and effectors of the immune response. NF-ĸB participates in response to inflammatory signals through T receptors, TNF receptors, and IL-1 receptors [40–42]. CREB is one of the best understood phosphorylation-dependent transcription factors (CREB) [16]. In effector T and B cells, immune receptor signals induce within minutes a rise of intracellular Ca++, the activation of the phosphatase calcineurin, and the

that *BCL6* may function in a "hit-and-run" role in lymphomagenesis [8].

*B-cellular differentiation and lymphomagenesis ([25], p. 1418).*

**80**

**Figure 2.**

#### **Figure 3.**

translocation of NFAT transcription factors from cytosol to nucleus; the induction of NFATc1/αA takes place during the G1 phase of cell cycle [43, 44]. The NFAT signaling pathway oversees different aspects of cellular functions; NFAT has a function like calcium sensor, including calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates different cellular functions such as cell survival, proliferation, migration, invasion, and angiogenesis [44, 45].

TCF/LEFs are multifunctional proteins that use their sequence-specific DNAbinding and context-dependent interactions to specify which genes will be regulated by Wnts. The TCF/LEF families have been shown to regulate the expression of specific genes, such as c-Myc and Cyclin D1 [46]. These transcription factors are interdependent and closely linked with each other to form a network in the above signaling pathways, which regulate the entire process of osteoblast proliferation and differentiation [14]. Normally, these factors appear to be involved in the physiological activation response of lymphocytes before controlling the growth of malignant cells [47, 48].

Proliferation, differentiation, and apoptosis are associated with different types of lymphoma and chromosomal translocations. Each lymphoma has a separate proliferation of the site, which is most clearly described in the follicular lymphoma that proliferates in the follicle. Special chromosomal translocations are associated with

*Oncogene path for three subtypes of DLBCL ([25], p. 1421).*

each type of lymphoma. *BCL1* translocation results in disturbed cell cycle regulation. *BCL2* and API2-MALT1 have an antiapoptotic function [49]. API2-apoptosis inhibitor 2-MALT1 (mucosa-associated lymphoid tissue lymphoma translocation gene 1)-induced NF-kappaB activation may contribute to antiapoptotic action probably through NF-kappaB-mediated upregulation of apoptotic inhibitor genes [49].
