**3. Therapeutic implications**

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)

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

Burkitt lymphoma t(8;14)(q24;q32) c-MYC overexpression

**Errors in class switch recombination**

t(8;14) (q24;q32), t(2;8) (p12;q24),

BCL6 rearrangement—multiple

t(8;22) (q24;q11

partner genes

**Resulting event**

overexpression

MALT1 dysregulation

c-MYC overexpression

BCL6 dysregulation

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/

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

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 recur-

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].

DLBCLs display activating mutations in the PIK3CA domain of PI3K [107].

**Errors in VDJ recombination**

(q32;q21)

t(11;18)(q21;q21), t(14;18)

Mantle cell lymphoma t(11;14)(q13;q32) Cyclin D1

Follicular lymphoma t(14;18)(q32;q21) BCL2 overexpression

CARD11 complex activates the classical NF-κB pathway (**Figure 2A**) [108].

affected by knockdown of BTK [95].

Marginal zone lymphoma of

28 Hematology - Latest Research and Clinical Advances

GCB-diffuse large B-cell

ABC-diffuse large B-cell

MALT type

lymphoma

lymphoma

neoplasms.

rent mutation requires further investigation [3, 40, 42, 48].

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

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 signaling, and autonomous signaling.

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].

Ibrutinib, a BTK inhibitor has demonstrated durable clinical responses in relapsed/refractory CLL patients, including those with the high-risk del(17p) cytogenetic abnormality. Durable clinical responses have also been demonstrated MCL and DLBCL [97, 114]. Several oral SYK inhibitors, including fostamatinib, entospletinib, and cerdulatinib, are being assessed in clinical trials [119].

**References**

Nature Immunology. 2015;**16**(4):343-353

of America. 2015;**112**(44):13447-13454

Journal of Experimental Medicine. 2000;**191**(1):5-8

The Journal of Experimental Medicine. 1993;**177**(4):1009-1020

mechanisms. Immunological Reviews. 2010;**237**(1):22-42

rule in V(D)J recombination. Cell. 1996;**85**(1):107-113

recombination. Nature. 2006;**442**(7101):466-470

tion. Nature. 2008;**451**(7180):841-845

Reviews. Cancer. 2016;**16**(6):387-398

bination. Annual Review of Immunology. 2008;**26**:261-292

mutations at sites of class switching. Nature. 2001;**414**(6864):660-665

result from mistakes in VDJ joining. Science. 1985;**229**(4720):1390-1393

nology. 2016;**39**:96-102

2002;**108**(6):781-794

resistance. Translational Cancer Research. 2017;**6**:S529-S532

[1] Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system.

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

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

31

[2] Gazumyan A et al. Activation-induced cytidine deaminase in antibody diversification and chromosome translocation. Advances in Cancer Research. 2012;**113**:167-190

[3] Navarrete MA, Oppezzo P. The pathogenesis of follicular lymphoma, beyond apoptosis

[4] Kenter AL et al. AID hits the jackpot when missing the target. Current Opinion in Immu-

[5] Young RM et al. Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. Proceedings of the National Academy of Sciences of the United States

[6] Carsetti R. The development of B cells in the bone marrow is controlled by the balance between cell-autonomous mechanisms and signals from the microenvironment. The

[7] Tiegs SL, Russell DM, Nemazee D. Receptor editing in self-reactive bone marrow B cells.

[8] Vettermann C, Schlissel MS. Allelic exclusion of immunoglobulin genes: Models and

[9] van Gent DC, Ramsden DA, Gellert M. The RAG1 and RAG2 proteins establish the 12/23

[10] Ma Y et al. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell.

[11] Bredemeyer AL et al. ATM stabilizes DNA double-strand-break complexes during V(D)J

[12] Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recom-

[13] Petersen S et al. AID is required to initiate Nbs1/gamma-H2AX focus formation and

[14] Liu M et al. Two levels of protection for the B cell genome during somatic hypermuta-

[15] Lieber MR. Mechanisms of human lymphoid chromosomal translocations. Nature

[16] Tsujimoto Y et al. The t(14;18) chromosome translocations involved in B-cell neoplasms

All these new drugs share a pattern of response resulting in nodal reduction and increased lymphocytosis. This phenomenon may reflect unique properties such as micro-environment modulation, and activity on the proliferative pools existing in the bone marrow and lymph nodes [74, 120].
