BCR signaling is of critical importance for normal B cell performance at all different stages of their development. BCR can induce a wide array of cellular responses related to the complexity of the intracellular BCR signaling network. Individual features of BCR signaling are highly dependent on a specific stage of B cell development and activation status [11]. Importantly, pre-BCR, which is structurally similar to BCR but contains a surrogate light chain (SLC) made up of the invariant proteins λ5 (CD179b) and VpreB (CD179a) instead of the Ig light chain in BCR [12], is transiently expressed in early developmental stages and is necessary for pro-B to pre-B transition and pre-B cell expansion [13,14]. Correct assembly and proper SLC replacement with the conventional light chain in pre-BCR is an imperative for further B cell development [15].

BCR signaling is involved in the prevention of naïve B cell premature activation and expansion of autoreactive clones. At the same time, low-level “tonic” BCR signaling is essential for naïve B cell survival [16]. BCR antigen binding promotes mature B cell activation and further differentiation of naïve B cells via activation of PLC-γ2, PI3K/AKT and MAPK signaling pathways [17]. To ensure proper functionality of activated B cells, BCR signaling sustains survival, stimulates cell growth, and supports other related cellular adaptations via an array of signaling cascades including Ca²⁺ signaling, NF-κB activation, PI3K/AKT/mTOR, NFAT, ERK, and MAPK signaling [18]. Furthermore, BCR is vital for antigen presentation and subsequent T cell response activation and for B cell differentiation into antibody-producing plasma cells [19]. In particular, BCR-mediated antigen internalization is followed by intracellular antigen processing and subsequent surface presentation to CD4⁺ and CD8⁺ T cells [20]. BCR signaling also critically regulates activation-induced cytidine deaminase (AID)-mediated immunoglobulin class switch recombination [21,22]. Combination of activated BCR signaling with either a T cell-dependent (follicular T helpers) or T cell-independent (lipopolysaccharides or glycolipids) signal is crucial for B cell differentiation into antibody-secreting plasma cells or memory B cells [23]. BCR signaling driven plasma cell differentiation requires transcription factor Ets1 downregulation via Lyn-, PI3K-, BTK-, IKK2- and JNK-dependent pathways [24].

Additionally, BCR signaling contributes to the regulation of multiple other cellular processes in normal B cells including metabolism. For instance, it induces PI3K/AKT-dependent activation of glycolysis, oxidative phosphorylation, and glucose uptake [25,26]. BCR signaling also activates c-Myc with resulting enhancement of glycolysis and mitochondrial biogenesis [27]. BCR-initiated Ca²⁺ mobilization regulates metabolic reprogramming of naïve B cells which is required for their growth and further differentiation [18]. Maintenance of the balance between cellular growth and catabolic and anabolic processes is critical for correct B cell functionality and is primarily sustained via c-Myc and mTORC1 activity (which are both adjusted through BCR signaling) [28]. Importantly, BCR signaling was also implicated in metabolic regulation via autophagy upregulation [29]. BCR-mediated autophagy has been reported to be required for B cell activation [28].

Besides survival, activation, and proliferation, BCR signaling may prime B cells to anergy and cellular death to ensure B cell tolerance [30]. For instance, BCR signaling has been suggested to serve as a B cell quality control. Only moderate-intensity BCR signaling promotes positive selection, while BCR ligation downregulates BCR expression, reduces pro-survival PI3K/AKT signaling, and provides negative selection [31]. Inappropriately activated BCR may lead to B cell apoptosis [32]. BCR-mediated pro-apoptotic signaling has been associated with Ca²⁺-dependent and mitochondrial pathways [30].

Therefore, not only the type of BCR signaling, but also its intensity varies during B cell development and can determine the cell fate of B cells and their involvement in the immune response.

According to the recently updated 5th classification of lymphoid neoplasms (the World Health Organization Classification of Haematolymphoid Tumours), B-cell malignancies include the following categories: tumor-like lesions with B-cell predominance, precursor B-cell neoplasms (B lymphoblastic leukemias), mature B-cell neoplasms, and plasma cell neoplasms and other diseases with paraproteins [33]. Mature B-cell neoplasms include, e.g., pre-neoplastic and neoplastic small lymphocytic proliferations (e.g., chronic lymphocytic leukemia, CLL), multiple types of non-Hodgkin lymphomas (NHLs), and Hodgkin lymphomas [33]. The most common subtypes of NHL are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), diagnosed in approximately 25–30% and 20% of NHL patients, respectively [34,35,36,37]. In most cases, B-cell-derived tumors retain surface expression of BCR which variably supports malignant cell growth and survival [38,39]. BCR signaling has been shown to drive the growth and evolution of B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and multiple types of NHLs [12,40,41,42]. Pathogenic BCR signaling has been extensively studied and clearly demonstrated for DLBCL. Additionally, there is evidence that BCR supports tumor cell growth and survival in mantle cell lymphoma (MCL), FL, Burkitt’s lymphoma, and marginal zone lymphoma [43,44,45,46].

BCR signaling supports tumor cell growth and survival via various mechanisms. The first described tumorigenic mode of BCR signaling was the so-called “chronic active” BCR signaling triggered by self-antigen binding. Chronic active BCR signaling supports the viability and growth of malignant B cells mainly through the NF-κB signaling pathway [47,48]. Recently, it was shown that frequent lymphoma-associated mutations of MYD88 (myeloid differentiation primary response 88) adaptor protein lead to its spontaneous association with Toll-like receptor 9 (TLR9) and BCR, forming a My-T-BCR complex capable to trigger NF-κB activation [49]. Moreover, it was shown that lymphoma growth is also supported by antigen-independent, constitutive, lower intensity “tonic” BCR signaling. Tonic BCR signaling supports the growth and survival of tumor cells mostly via the PI3K/AKT/FOXO1 signaling pathway [50,51]. Antigen-independent cell autonomous BCR signaling with features of antigen-triggered BCR signaling was identified in CLL [40]. Importantly, in DLBCL, the type of BCR signaling (antigen driven or similar vs. tonic) reflects gene expression profiling-based cell-of-origin classification into the activated B cell like (ABC) DLBCL subtype and germinal center B cell like (GCB) DLBCL subtype, respectively [52].

Given the importance of BCR signaling in B-cell derived malignancies, its inhibition is one of the novel therapeutic approaches. It is represented mainly by three BTK (Bruton’s tyrosine kinase) inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) approved and frequently used in the treatment of certain B-cell derived neoplasms. BTK inhibitors are effective; however, their toxicity and common resistance development represent substantial challenges that motivate the search for additional BCR signaling targeted inhibitors [53].

Important considerations regarding types of BCR signaling come from genomic studies, as documented in DLBCL. Distinct patterns of BCR signaling are reflected in tumor mutational patterns, which further expand the above-mentioned cell-of-origin DLBCL classification. Based on the spectrum of somatic alterations, genomic studies identified five to seven distinct genetic DLBCL subtypes [54,55,56,57,58]. The MCD (combined MYD88^L265P and CD79B mutations), N1 (mutated NOTCH1), and A53 (aneuploid and TP53 inactivation) subtypes are significantly overlapping with the ABC DLBCL subtype, whereas EZB (mutated EZH2 and translocated BCL2), ST2 (mutated SGK1 and TET2), and BN2 (translocated BCL6 and mutated NOTCH2) are overlapping with GCB DLBCL [56]. Alternative classifications were published by Chapuy et al., including clusters 1 to 5 (BN2-DLBCL, A53-DLBCL, EZB-DLBCL, ST2-DLBCL, and MCD-DLBCL, respectively); and by Lacy et al., including MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2 clusters [55,58]. Pedrosa et al. later attempted to unite and simplify the existing classifications through the assessment of the mutational status of only 26 genes and BCL2 and BCL6 translocation status to facilitate their clinical implementation (two-step genetic DLBCL classifier; 2-S). The suggested 2-S subtypes are N1^2-S, EZB^2-S, MCD^2-S, BN2^2-S, and ST2^2-S [54]. Importantly, none of the above-mentioned genetic studies were able to assign all cases, leaving a substantial proportion of tumors unclassified. On the other hand, genetic studies provided insights into the contribution of CD79a and CD79b (and their mutations) towards tumorigenesis and lymphoma development [54,55,56,57,58].