*2.2.4. Mutations in the BCR signaling cascade*

In addition to the natural activation, BCR signaling can be induced by acquired mutations.

Different ABC DLBCL cases carry diverse activating mutations in the BCR pathway (**Table 1**). Mutations of a critical tyrosine residue in the ITAM of CD79B increase the signaling response by interfering with activation of LYN. In this subset of ABC DLBCL cells, PI3K and BTK signaling remain essential for NF-κB activation [104]. About 10% of ABC DBCL cases show activating mutations of CARD11, a key protein that connects BCR activation to NF-κB signaling. This mutation is sufficient to intrinsically activate survival signaling in the malignant B cells and obviates the need for upstream BCR signaling [103]. Loss of function mutations in the tumor suppressor A20 contributes to NF-κB pro-survival signaling have also been described in ABC DLBCL and CLL cases [105, 106].


**Table 1.** Recurrent translocations and their link to V(D)J recombination or class switch recombination in mature B-cell neoplasms.

Although germinal center B (GCB) DLBCL seems independent of BCR signaling, still may require intrinsic activation of the PI3K pathway (**Table 1**). Some germinal center B (GCB) DLBCLs display activating mutations in the PIK3CA domain of PI3K [107].

**3. Therapeutic implications**

Chronic lymphocytic

Marginal zone lymphoma of

GCB-diffuse large B-cell

ABC-diffuse large B-cell

contribution to pathogenesis.

leukemia

MALT type

lymphoma

lymphoma

**Antigendependent BCR signaling**

**Table 2.** Pathogenic activation of the B-cell receptor signaling cascade.

signaling, and autonomous signaling.

In malignancies, in which chromosomal translocations result in the constitutive overexpression of oncogenes, the use of targeted therapy in these oncogenes represents a very attractive concept. One example is venetoclax, a highly potent and selective oral BCL-2 antagonist.

**Tonic BCR signaling**

Follicular lymphoma + − − CD79B, CARD11, CXCR4,

Burkitt lymphoma − ++ − NF-kB independent

The estimated relative contribution of antigen-dependent, tonic, and autonomous BCR signaling to the pathogenesis is represented as follows: [++] = major contribution, [+] = potential contribution, [−] = no evidence of contribution or minor

++ + +++ BTK, PLCγ2

++ − − MALT1

− ++ − PI3K, PTEN

− + ++ ITAM, CARD11, NF-kB

**Autonomous BCR signaling**

The Antigen Receptor as a Driver of B-Cell Lymphoma Development and Evolution

**Recurrent mutations in the signaling pathway**

29

SYK, BTK

http://dx.doi.org/10.5772/intechopen.72122

dependent

The link between antigen-driven BCR activation and lymphomagenesis immediately suggest that the identification and elimination of the putative antigen could result in tumor regression. The induction of complete remission of gastric MZL by antibiotic therapy aimed to eradicate *H. pylori* represents a paradigmatic example of this idea [70]. However, the identification of cognate foreign antigens has been extremely difficult. Another therapeutic concept is the idea of disrupting the interaction of the BCR with its antigen by the generation of anti-idiotype antibodies. Despite promising results in early phase clinical trials, phase III studies failed to show a substantial benefit of this approach when used as consolidation therapy [49, 113]. The evident dependence of B-cell lymphomas on the BCR signaling pathway establishes BCR signaling blockade as a rational and disease-specific therapeutic approach. This strategy has the potential to block all three BCR signaling mechanisms: antigen-dependent signaling, tonic

The BCR signal can be blocked by specific inhibitors of essential tyrosine kinases of the signaling cascade such as BTK [114] or SYK [115, 116], or by blocking integration point of signals originating from cell surface receptors. PI3Kδ represents one of this integration points and idelalisib, a small molecular PI3Kδ inhibitor has shown clinical efficacy in CLL and FL [117, 118].

Venetoclax has proven to be highly active in patients with CLL, FL, and MCL [112].

Another example of a transition from a dependence on extrinsic BCR activation to intrinsic activation has been described in MALT lymphomas (**Table 2**). In advanced cases, the t(11;18) chromosomal results in a fusion transcript of API2-MALT1 and the t(1;14) leads to overexpression of BCL10 under the control of the Ig heavy chain locus. Consequently, MALT1/BCL10/ CARD11 complex activates the classical NF-κB pathway (**Figure 2A**) [108].

Burkitt lymphoma (BL) seems dependent upon tonic BCR survival signaling through PI3K but not upon the NF-κB pathway. The hallmark of BL is a translocation of MYC to the Ig heavy chain locus. However, MYC has strong pro-apoptotic effects and requires activation of pro-survival signaling through the PI3K pathway. In BL activation of PI3K resembles the tonic signaling in normal resting B cells [95, 96]. Consistently, BL cells are sensitive to genetic knockdown of CD79A or SYK and pharmacologic inhibition of PI3K, however, are not affected by knockdown of BTK [95].

In follicular lymphoma, at least half of the patients show evidence of mutations in the interconnected BCR and CXCR4 signaling pathways such as mutations in CD79B, CARD11, CXCR4, SYK, BTK, and HVCN1 [3, 109]. Considering the unique characteristics of the BCR in this lymphoma type, such as high hypermutation rates, distinctive selection patterns, mannosylation of the antigen binding site and autoantigen binding, the understanding of the precise interplay between the tumor dependence on a functional BCR and the presence of this recurrent mutation requires further investigation [3, 40, 42, 48].

In CLL there is evidence for mutations in BTK and PLCγ2 that may confer resistance to BTK inhibition [110]. Despite the general consensus on the absence of somatic mutation on both CD79A and CD79B in CLL, one study has reported mutations in CD79B [111].


The estimated relative contribution of antigen-dependent, tonic, and autonomous BCR signaling to the pathogenesis is represented as follows: [++] = major contribution, [+] = potential contribution, [−] = no evidence of contribution or minor contribution to pathogenesis.

**Table 2.** Pathogenic activation of the B-cell receptor signaling cascade.
