*2.2.3. Autonomous signaling and lymphomagenesis*

domains of the mannose receptor and dendritic-cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), which results in stimulation of FL cells [84]. It has also been demonstrated that V-region mannosylation conferred the ability of B cells to be activated by soluble bacterial lectins from common opportunistic pathogens such as *Pseudomonas aeruginosa* or *Burkholderia cenocepacia* while disrupting the initial receptor specificity for potential

The source of the antigen is not necessarily derived from an external pathogen as it has also been shown to derive from self-antigens. CLL BCRs can react with many different self-antigens, including antigens released by apoptotic cells [85, 86]. In addition, BCR derived from CLL patients can bind to a conserved epitope within the second framework region (FR2) of their own BCR [87]. About 26% of FL cases recognize autoantigens, and the interaction with certain self-antigens such as myoferlin can induce BCR-mediated signaling *in vitro* [65]. It has also been demonstrated that interaction of the BCR of ABC DLBCL with a self-antigen is essential for the survival of these lymphoma cells. This interaction may explain the microclu-

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 pro-

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 lym-

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

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].

apoptotic BCL2 family member, BCL2L11, and the cell-cycle inhibitor p27 [92].

signaling differ from those induced by BCR engagement in BL cells [96].

sters observed in the plasma membrane of ABC DLBCL cells [5, 88].

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

phoma (GCB-DLBCL) [93, 94].

autoantigens [64].

26 Hematology - Latest Research and Clinical Advances

Autonomous antigen-independent, BCR signaling is a survival mechanism characteristic of the pre–B-cell receptor [57, 98]. However, immature and mature B cells with BCRs, that recognize multiple self-antigens, may also induce autonomous signaling and selective expansion of B cell in a manner comparable to the pre-BCR [56]. This functional similarity between autoreactive BCRs and the pre-BCR suggests that recognition of self-antigens might not only play a role in the positive selection of early B cells, but also could contribute to lymphomagenesis [87, 99–101].

Autonomous signaling has been proposed as a novel oncogenic mechanism in chronic lymphocytic leukemia (CLL) and diffuses large B-cell lymphoma (DLBCL) [87, 100, 101]. BCR, derived from both mutated and unmutated CLL cases, expressed in a cellular system designed to measure BCR signaling cascade activation, show signaling properties that are equivalent to those of the pre-BCR [87]. This striking signaling property is dependent on the antigen-binding site of the clonal BCR and an internal motif in framework region 2, a part of the structural BCR backbone [102].

The gene expression profile of activated B-cell (ABC) type of DLBCL resembles that of mature B cells upon stimulation via their B-cell receptor (BCR). In up to 30% of ABC DLBCL cases, this signature can be explained by gain-of-function mutations in CD79A, CD79B, or CARD11 [103]. However, in patients without CARD11 mutations activation of the BCR may occur through autonomous signaling. We have recently demonstrated the presence of autonomous BCR activity in 72% of non-GCB DLBCL, including primary mediastinal DLBCL [100, 101]. This finding may provide a complementary or alternative explanation to the characteristic gene expression signature of ABC DLBCL.

These findings in CLL and DLBCL support the concept of the BCR acting as a true oncogene, despite being structurally normal and solely characterized by this autonomous signaling property.
