*2.2.2. Tonic B-cell receptor signaling and lymphomagenesis*

The tonic B-cell receptor signaling (BCR) is thought to provide an antigen-independent constitutive baseline signal essential for B cell survival and development [58, 89]. Although the detailed molecular mechanisms regulating tonic signaling remain to be defined, current evidence highlights the central role of the SYK tyrosine kinase and the balance between BCRassociated SYK activation and protein tyrosine phosphatase (PTP)-mediated SYK inhibition [53, 90]. The tonic signaling transmitted via SYK appears to activate the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway [91]. The inhibition of the tonic BCR signal results in increased activation of FOXO1 and increased expression of its target genes, including the proapoptotic BCL2 family member, BCL2L11, and the cell-cycle inhibitor p27 [92].

Evidence about the use of tonic antigen-independent type of BCR signaling by malignant B cells is reported for Burkitt lymphoma (BL) and germinal center B diffuse large B-cell lymphoma (GCB-DLBCL) [93, 94].

In BL, PI3K signals promote the survival and proliferation of BL cells [95]. One study demonstrated by quantitative phosphoproteomics, in which phosphorylation events in tonic BCR signaling differ from those induced by BCR engagement in BL cells [96].

In DLBCL, BCR signaling differs between the germinal center B-cell (GCB) subtype, which is insensitive to Bruton's tyrosine kinase inhibition by ibrutinib, and the activated B-cell (ABC) subtype [97]. As recently reported, the replacement of antigen-binding regions of the BCR has no effect on BCR signaling in GCB-DLBCL cell lines, which supports the hypothesis of the use of tonic BCR signaling by this DLBCL subtype [94]. Unlike antigen-driven BCR signaling, tonic BCR signaling requires specific phosphorylation of CD79A. This finding provides a rationale for the development of novel molecular targeted drugs for the treatment of DLBCL [94].
