2.1. BCR Signaling

BCR signaling is very important for many types of NHLs, which shows how essential it is in the lymphomagenesis process. It is imperative that molecular clinicians understand the critical role of the BCR in the appropriate growth and maturation of B cells [10], so they can develop strategies to combat the lymphoma. The efficacy of BCR signaling and the activation of cofactors such as Toll-like receptors (TLR), B-cell activating factor (BAFF), and CD-40 are critical for B-cell responsiveness and survival during the germinal center response. In order for mature B cells to remain viable during periods of inactivity, they require a fundamental “tonic” BCR signal. On the other hand, antigens activate BCRs, which subsequently induce the proliferation, maturation, and production of antibodies by B cells [9, 10].

A functional BCR comprises an immunoglobulin that is membrane-bound along with two co-receptors, Ig alpha (CD79a) and Ig beta (CD79b) [3]. The BCR finds an antigen on both healthy and cancerous B cells and either sends a steady signal through the PI3K pathway or starts other pathways to work. The binding of an antigen to the BCR leads to the cross-linking of multiple receptors and morphological alterations. ITIMs of CD79a and CD79b are immunoreceptor tyrosine-based activation motifs that get tyrosine phosphorylated by Lyn and other tyrosine kinases (SFKs) from the SRC family. The phosphorylation events of spleen tyrosine kinase (SYK) initiate the materialization of a functional signalosome complex. Adaptor proteins and a variety of tyrosine kinases are involved in the complex’s assembly [11]. The signal is sent by tyrosine kinases like BTK and phospholipase Cγ2 (PLCγ2). Adaptor proteins like B-cell linker (BLNK) and B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) control how the signal is spread [3, 11]. Furthermore, phosphatases play a role in BCR signaling regulation. SH2-containing protein tyrosine phosphatase 1 may inhibit SRC and SYK. In contrast, the SH2-containing protein tyrosine phosphatase 2 (SHP2) is important in signaling, particularly in the ERK pathway [9, 11]. In general, the complex network of proteins that are involved in BCR signaling guarantees a well-regulated and balanced immune response. Various autoimmune diseases and malignancies can result from the dysregulation of these pathways. Understanding the precise mechanisms of BCR signaling can provide valuable insights for therapeutic interventions that target these conditions.

2.2. PI3K–AKT–mTOR Pathway

Numerous biological functions, such as metabolism, angiogenesis, cell proliferation, survival, and differentiation, depend on the PI3K/AKT/mTOR pathway [12]. After the BCR is depleted, activation of the PI3K pathway is enough to sustain the survival of mature B cells at rest. Consequently, it is proposed that the primary component of the tonic BCR signaling is the PI3K signal transduction. Moreover, even though PI3K itself is commonly altered, the tonic signal is crucial for a large number of B-cell malignancies. The adaptor protein BCAP transfers the BCR signal to a PI3K heterodimer made up of a catalytic and a regulatory [13]. Additionally, multiple effectors are implicated. PI3K and BTK collaboratively activate NF-κB. In contrast, AKT serves as the link between PI3K and mTOR pathways. It turns on phosphoinositide-dependent kinase-1 (PDK1), which then binds and phosphorylates AKT by working with mTOR complex 2 (mTORC2). After that, AKT phosphorylates mTORC1 and turns off Forkhead/winged helix box class O (FOXO), which helps cells move through the cell cycle and stay [14].

Two well-known products such as ribosomal S6 kinase (S6K) and the eIF4E binding protein (4E-BP1) also modulate the mTORC1. A cascade of events follows leading to protein synthesis, nutrient response, and several additional functions essential for rapid growth. Additionally, the negative feedback mechanisms that diminish upstream PI3K-AKT signaling include the inactivation of insulin receptor substrate 1 (IRS-1), the suppression of mTORC2. The mTORC pathway is also dependent on S6K, and the phosphorylation of the adaptor protein glycine-rich RNA-binding protein 10 (GRB10) [12, 13, 15]. Understanding the mechanisms that govern mTORC1 signaling is critical for developing targeted therapies. Investigating the consequences of reduced PI3K-AKT signaling may provide insights into potential treatment strategies for BCLs.

2.3. NF-κB Pathway

The NF-κB pathway plays a crucial role in B-cell proliferation and survival by counteracting apoptotic signals [16]. Different types of BCLs have abnormal NF-κB activation, which leads to increased cell cycling and decreased apoptosis. In addition to this, PLC2, BTK, and the adapter protein BLNK promote the activation of the canonical NF-B pathway. Along with diacylglycerol (DAG) and more calcium moving inside cells, PLCγ2 activity causes the classical isoform PKCβ to phosphorylate CARD11 [17]. BCL-10 initiates the activation of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Following multimerization with CARD11, the complex recruits TNF receptor–associated factor 6 (TRAF6) and TAK1. A process involving ubiquitin is used by TRAF6 to connect with IKK, while TAK1 helps IKK’s activation cycle phosphorylation. The inhibitory protein IκB is phosphorylated by IKK. This causes it to be polyubiquitinated and then broken down by proteases, and then, transcription factor NF-κB moves into the cell [18, 19].

The different NF-κB pathway turns on IKKs, which directly phosphorylate and partially break down certain NF-κB subunits. NF-κB1 (p50), NF-κB2 (p52), c-Rel, RelA (p65), and RelB (p52) form heterodimers. Nucleus-localized heterodimeric NF-B transcription factors initiate target gene transcription. NF-κB target genes encompass cell cycle regulators, antiapoptotic, inflammatory, and immunoregulatory molecules, along with negative feedback regulators that impede upstream pathway activation. The NF-κB pathway turns on proteins in the BCL-2 family that stop cell apoptosis, as well as MYC and cyclin D1, which control the cell cycle. Immunoregulatory cytokines are made up of interleukins (ILs) like IL2, IL6, and IL10. These ILs activate growth receptors either directly or indirectly [5, 20]. NF-κB functions as a critical regulator of immune responses and body homeostasis maintenance. Its complex role in multiple pathways underscores its significance in both normal physiological functions and pathological conditions such as cancer. In lymphomas, dysregulation of NF-κB signaling can result in uncontrolled cell proliferation and inflammation. Understanding the intricate role of NF-κB in immune responses is critical for the development of targeted therapies for various lymphomas.

2.4. JAK-STAT Signaling

The JAK and STAT pathways are primarily activated by ILs. Both autocrine and paracrine mechanisms release them. The regulation of cell proliferation, survival, differentiation, and immune response is contingent upon the JAK-STAT pathway. Elevated serum levels of various ILs accompany BCR signaling in NHLs. When there are changes in the NF-κB pathway in ABC-DLBCLs, IL-6 or IL-10 is made, which raises the activity of growth factors [21, 22]. Cytokine binding may cause basally inactivated cognate receptors to dimerize. The activation of intracellular JAKs leads to the cross-phosphorylation of the receptor. JAKs have the potential to phosphorylate STAT proteins as a result of their binding to them. For example, the binding of IL6 or IL10 to the receptor in NHL transmits a signal to STAT3 via JAKs [21]. JAKs may also activate the PI3K, mTOR, and MAPK pathways; however, their activity is halted by either phosphatase activation or receptor internalization [22, 23].

Furthermore, phosphorylated STATs dimerize and shift to the nucleus, functioning as transcription factors. In addition, STATs control suppressors of cytokine signaling (SOCS) transcription, as well as proliferative and surviving genes. SOCS 1–7 are part of the negative feedback loops in this pathway. They halt STAT signaling by directly linking to JAK, thereby preventing more STAT phosphorylation. Furthermore, STAT protein inhibitors (PIAS) interact directly with STATs to impede their transcriptional function [22]. Researchers have identified STAT signaling pathway dysregulation as a factor in various cancers, including lymphoma. Understanding how SOCS and PIAS regulate this pathway is critical for developing targeted B-cell NHL therapies.

2.5. Apoptosis Signaling Pathway

Apoptosis refers to the PD of a cell, distinguishing it from other forms of cell death, including autophagy, necroptosis, netosis, pyroptosis, necrosis, and ferroptosis. Apoptosis induces various morphological changes in the cell, including a reduction in the size of the mitochondria and nuclei. Apoptosis is characterized by a reduction in cell function and size, a phenomenon referred to as “blebbing.” During blebbing, certain regions of the cell membrane encapsulate the cellular contents. Phagocytosis rapidly removes apoptotic cells from the site, thereby mitigating the robust inflammatory response. A TNF-regulated extrinsic death receptor pathway can initiate apoptosis. The intrinsic mitochondrial pathway can also mediate this process. The mitochondria that are helped by tBID (truncated BH3-interacting domain protein) are where these pathways come together [24]. For example, tumor necrosis factor receptor 1 (TNFR1) and Fas are two death receptors that are activated when ligands bind to them. In the beginning, Fas connects to FADD (Fas-associated via death domain) and then joins with caspase 8. This makes a signaling complex that can start apoptosis. This facilitates apoptosis by directly activating caspase 3 and caspase 7, or indirectly triggering caspase pathways reliant on mitochondrial mechanisms [25]. Compared to the Fas-mediated pathway, TNFR1-mediated apoptosis is more conducive to the incorporation of the intricate TRADD (TNFRSF1A-associated via death domain) and TRAF2. This causes cell death by activating NF-κB via IKK [26]. Hypoxia, DNA damage, and oncogenic stress trigger apoptosis more swiftly in the intrinsic apoptotic pathways. In both upstream and downstream cascades, p53, DNA checkpoint proteins, and BCL2 family members work together to control and send signals along this pathway. This ultimately facilitates the activation of caspase 3 and caspase 7, resulting in results similar to those obtained via the extrinsic route [25]. Besides apoptosis, MYC transcription factors directly and indirectly govern cell proliferation, metabolism, differentiation, and oncogenes. Consequently, the majority of cancers arise from C-MYC dysregulation. Rapidly proliferating cancer cells inherently produce increased levels of oncogenic MYC, resulting in diminished genomic stability. This indicates that late-stage or recurring cancer cells, which are likely to have elevated MYC levels, must possess increased DNA damage. In advanced cancer cells, chemotherapy and radiation induce genomic instability, prompting oncogenic MYC to develop an efficient DNA repair mechanism. Because of its involvement in carcinogenesis, MYC inactivation should reduce cancer cell survival [27].

In summary, B-cell neoplasms frequently disrupt the normal signaling pathways used by B cells for antigen recognition. This ensures the continuous activation of pathways that facilitate survival. BCR is crucial for the regulation of a variety of processes in normal B cells, such as proliferation, differentiation, apoptosis, and cell migration. Proximal BCR signaling activates the PI3K, NF-B, NFAT, and MAPK pathways. Other signaling events occur at greater distances. Signal transmission through the MAPK pathways involves the activation of multiple pathways, including MAPK, ERK, JNK, and p38 [23]. All BCR-induced pathways facilitate the survival and proliferation of B-lymphocytes.

3.1. DLBCL

DLBCL is a neoplasm that features medium- to large B-lymphoma cells that display a diffuse proliferation pattern. DLBCL encompasses distinct condition entities defined by specific clinical, abnormal, and biological characteristics. We diagnose DLBCLs not otherwise specified, commonly referred to as DLBCL, when they fail to fit into a specific classification. DLBCL represents the most prevalent subtype of B-lymphoma, comprising 25%–35% of all B-NHLs [2, 3]. The R-CHOP regimen, comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, serves as the standard treatment for patients with DLBCL, achieving a cure rate of 50%–70% among those who receive it. Nonetheless, the remaining patients either exhibit resistance to R-CHOP treatment or experience disease relapse following a complete response (CR). Comprehending the biology of DLBCL is crucial for identifying individuals who are unlikely to attain remission with R-CHOP and for exploring other treatment strategies. The discovery of different biological subtypes of DLBCL is a big step forward in research. The main way to classify DLBCL is into subtypes that are like germinal center B cells (GCB) or activated B cells (ABC). The two subtypes exhibit unique genomic profiles and correlate with varying clinical outcomes [29].

DLBCL genetics are complex; therefore, we focus on significant genetic mutations and their potential contributions to DLBCL pathogenesis. These target gene expressions significantly enrich ABC-DLBCL, a subtype of DLBCL, suggesting a critical role for deregulated constitutive NF-B. Genetic mutations in DLBCL drive a common pathway of deregulation, which in turn leads to constitutive NF-B activation. It has been demonstrated that mutations target the NF-κB signaling complex of CARD11, oligomerized BCL10 and MALT1, regulator A20, and the signaling complex of the BCR. Missense mutations in CARD11, particularly in the coiled-coil domain, are essential for the activation of NF-B, which in turn facilitates oligomerization [5, 29]. Twenty percent of ABC-DLBCLs deleted or mutated one negative regulator, A20. More than 20% of ABC-DLBCLs have somatic mutations in the BCR signaling proteins CD79A and CD79B. These mutations cause BCR signaling to stay active for longer, which starts complicated processes that are needed for tumor cells to grow and stay alive. ABC-DLBCL causes trisomy 3, 6q deletion, 18q amplification, 9 interstitial deletion, and 19 amplification. Certain gene changes imply secondary, substantially unregulated pathways. Most ABC-DLBCL patients lose just p16INK4A, indicating a dismal fate [30]. By turning PIP3 into inactive PIP2, the tumor suppressor PTEN may reverse this process. PTEN loss increases PIP3, which releases PI3K/AKT pathway inhibition. This route promotes cell growth, angiogenesis, and proliferation [13, 15].

Implications: Numerous studies have demonstrated that deletion or expression of PTEN has varying prognostic implications in DLBCL [6]. The study by Pfeifer et al. found that over 55% of GCB-DLBCL patients had deregulation of the pathway involving PI3K/AKT as a result of PTEN loss, compared to just 14% of non-GCB-DLBCL cases. In addition, 248 individuals with primary DLBCL who had this dysregulation had a dismal prognosis [48]. Contrarily, two large-scale studies of DLBCL patients found that PTEN mutation and deletion did not significantly affect clinical outcomes. Findings from this study provide credence to the idea that the MYC and PI3K/AKT/PTEN signaling pathways are independent and not sequential [8, 49]. In this subtype of DLBCLs, therapeutic interference with apoptosis protection is of the utmost importance. Interactions between MYC and certain miRNAs can change the expression of target genes. This throws off the balance of MYC signaling networks, especially between functions that cause cell death and functions that cause cell growth. This may indirectly lead to GCB-DLBCL [27, 31, 32]. MYC transcription factors regulate cell proliferation, metabolism, differentiation, and cancer genes directly and indirectly. Therefore, most malignancies including BCLs result from c-MYC deregulation. Rapidly growing cancer cells naturally make more oncogenic MYC, which makes the genome less stable. Cancer cells with high MYC levels tend to be in the late stages or return after treatment, which suggests that there must be more DNA damage in these cells. In advanced cancer cells, radiation and chemotherapy cause genomic instability, which oncogenic MYC compensates for by developing a highly efficient DNA repair system. Inactivating MYC should reduce cancer cell survival due to its role in carcinogenesis [27].

Mechanisms: It is essential to examine the mechanisms that trigger genetic mutations in DLBCL in order to comprehend the disease’s pathogenesis. About 80% of the mutations in DLBCL are due to age-related spontaneous deamination, according to an examination of mutational signatures. DLBCL causes changes in DNA via processes that are exclusive to B cells. The IGH locus may experience breakpoints caused by RAG1 and/or RAG2, which can result in gene fusions like IGH-BCL2. Only single-stranded DNA contains the enzyme activation-induced cytidine deaminase (AID). It changes cytosine residues to uracil residues, which lets somatic hypermutation and class-switch recombination happen. In addition to immunoglobulin DNA variables, AID targets other elements and switches recombination patterns. It targets actively transcribed genes, such as BCL6 and MYC, and interferes with their function. The shift region of IGH is where most breaks in the translocations of IGH-BCL6 and IGH-MYC occur. This suggests that AID-facilitated class-switch recombination is the process that leads to these translocations. AID induces BCL2 breaks in pre-B cells, although AID expression is lower than that observed in GCB. The RAG complex is not implicated due to the presence of a GC-rich motif within the BCL2 breakpoint region, which is not a target for the RAG complex. In DLBCL, AID-mediated off-target hypermutation may play a role in the development of oncogenic mutations. More than 50 percent of patients diagnosed with DLBCL exhibit hypermutations in nonimmunoglobulin genes. AID predominantly induces mutations in BCL2, PIM1, SGK1, and IGLL5, as demonstrated by a 2018 study. AID-induced mutations primarily manifest as single nucleotide substitutions, whereas deletions and duplications occur with lesser frequency. The data indicate a propensity for transversions as opposed to transitions, with the RGYW pattern receiving particular attention, implying its role in somatic hypermutation [29]. In DLBCL, MYC acts as a genetic and protein expression-based independent predictive marker. Recently, “high-grade BCL with MYC and BCL2 and/or BCL6 rearrangements” (HGBL-DH) was officially classified as a distinct entity by the World Health Organization (WHO). Numerous cancer centers recommend dose-intensive chemotherapy regimens due to the extremely poor prognosis associated with these lymphomas [50]. It is important to do further research on MYC mutations in BCL, particularly in refractory and relapsing pathways.

Clinical outcomes among individuals with DLBCL-administered R-CHOP exhibit significant heterogeneity, underscoring the need for further research to create more effective prognostic tools. Determining various genetic abnormalities will enhance risk stratification for individuals with DLBCL. Numerous studies have utilized genetic abnormality data to create prognostic models for DLBCL, potentially outperforming risk stratification methods that only use standard clinical indicators [29].

3.2. CLL/SLL

CLL is a prevalent B-cell malignancy characterized by significant heterogeneity in its clinical course, which can vary from indolent forms requiring no immediate treatment to rapidly progressive variants that exhibit therapeutic resistance [51].

CLL Genetics: Whole-genome sequencing (WGS) has enabled the characterization of the genomic terrain encompassing CLL. In total, 11 recurrent somatic copy number variations and 44 recurrently mutated genes have been identified. Some of these genes are PTPN11, ZNF292, IKZF3, SF3B1, FBXW7, ATM, TP53, FBXW7, SF3B1, CHD2, POT1, ARID1A, BXW7, and PTPN3.

Implications: The central pathways involved in CLL are RNA processing and export, MYC expression, and MAPK signaling. Furthermore, these analyses frequently implicate proteins that play a crucial role in the destruction of DNA signaling and repair. Patients who are secondary resistant to chemotherapy that damages DNA have higher levels of del(11q) and del(17p), as well as somatic mutations in ATM and TP53 that stop them from working. Underlying genes 9p13 contain an enhancer that, when mutated, can inhibit the activity of the B cell–specific transcription factor, PAX5 [33, 36]. BCR signaling is critical in the development of CLL. The BCR engages and signals, triggering pathways that control the destiny of normal or leukemia B cells. When the BCR is activated, it brings in kinases like SYK and SRC kinase LYN. These kinases change the shape of immunoreceptor tyrosine-based activation motifs (ITAMs) on CD79b and CD79a, two helper proteins in the BCR complex [52]. It is possible for adaptor proteins and other kinases, such as BTK and PI3K, to join the BCR accessory molecule complex when CD79a and CD79b ITAMs are phosphorylated.

Clinical Outcomes: Activation of these signaling molecules activates AKT/mTOR, NF-κB, and/or ERK. ZAP-70 might improve BCR signaling in CLL not by making more kinases active, but by making it possible for more kinases, like SYK, to join the BCR complex [5, 24]. In any event, ZAP-70’s relationship with aggressive illness is most likely due to the increased signaling capacity it provides [37].

3.3. BL

BL was first identified by Denis Burkitt in 1958 as a very aggressive BCL in children from Africa. BLs constitute 40 to 50 percent of lymphomas in pediatric populations, while they represent only 1 to 2 percent of lymphoma cases in adults [53]. BLs have uniform, extensively proliferating cells, as well as a starry-sky aspect. This is because tissue macrophages eat apoptotic debris. EBV infection is associated with all endemic cases, 15% of cases that occur sporadically, and 40%–50% of immunodeficiency-associated BLs, although the implications are still under investigation [55].

BL Genetics: BL frequently alters the gene MYC, with changes occurring in 70% of cases. These mutations commonly impact the transactivation domain of the gene. A significant number of these mutations are probably caused by AID, due to the close proximity of the immunoglobulin and MYC locus in BL. Certain mutations of the transactivation domain increase the capacity to convert cells and specifically hinder their ability to activate the proapoptotic protein Bim from the Bcl2 family. These mutants show a separation of MYC’s pro-proliferative function from its ability to trigger cell death. BL frequently exhibits TP53 inactivating mutations, with a prevalence of 35%. The selection of these mutations is likely due to the fact that when MYC is overexpressed in primary cells, it triggers apoptotic pathways that rely on TP53 [55]. There are reports of more intricate karyotypes and numerous genetic abnormalities such as p16, p53, RBL2/p130, BAX, and BCL6. However, the fact that some features of this disease are similar to DLBCL may lead to unique molecular changes that affect the control of important cellular pathways, making this disease molecularly distinct. The preponderance of these cases comprises the novel class of “BCL unclassifiable with characteristics intermediate between DLBCL and BL,” which is also referred to as “double-hit” lymphomas. These instances are distinguished by the rearrangement of both MYC and BCL2, and, to a lesser extent, MYC and BCL6 as well.

Clinical Outcomes: The patients have a poor clinical prognosis, and the overexpression of BCL2 may potentially significantly protect against apoptosis. BL has been associated with microRNAs, and the relationship between miRNAs and MYC is intricate [32, 55].

3.4. FL

FL is characterized by the translocation t(14; 18) (q32; q21)/IGH::BCL2, which is prevalent in 80%–85% of affected individuals. In contrast, t(2; 18) (p12; q21)/IGK::BCL2 and t(18; 22) (q21; q11)/BCL2::IGL are less frequent variant translocations.

FL Genetics: The overexpression of the BCL2 protein occurs due to the regulation of the BCL2 oncogene by immunoglobulin genes, which is the result of these translocations. In FL, deletions of chromosome regions 1p (15%–20%), 6q (20%–30%), 10q/PTEN (20%), and 13q (15%) are common secondary changes that make FL unique. Additionally, there are gains observed in 1q (25%), 2p (25%), 8q (10%), 12q (20%), and 18q (30%). Additionally, we note trisomies of chromosomes 7 (20%), 18 (20%–30%), and X (20%). Reports also reveal recurrent copy-neutral losses of heterozygosity (CN-LOH) at 1p (30%), 6p (20%), and 16p (20%–25%). The genes most often changed by somatic variants are those that control epigenetics and transcription (KMT2D, CREBBP, EP300, EZH2), JAK-STAT and NOTCH signaling (SOCS1, NOTCH1, NOTCH2), immune evasion (TNFRSF14), the BCR/NF-κB pathway (CARD11, TNFAIP3, CD79A, CD79B, MYD88), and cell growth and death (BCL2, TP53). Ten to twenty percent of patients develop an aggressive lymphoma, most commonly DLBCL, after histological transformation of FL. During the process, genomic changes happen, such as the addition of oncogenes like REL/BCL11A (2p16), BCL6 (3q27), and MYC (8q24), and the deactivation of tumor-suppressing genes such as TP53 (17p13) and CDKN2A/B (9p21). While the t(14; 18) (q32; q21) is widely regarded as the principal genetic occurrence in FL, the BCL2 translocation (BCL2-FL) is absent in approximately 10%–15% of all FL patients [33].

3.5. MCL

MCL is an uncommon kind of cancer that originates from B cells and has diverse clinical characteristics.

MCL Genetics: Molecularly, the most prevalent type is the conventional MCL (cMCL), which is defined by the lack of IGHV mutations, high SOX11 expression, and a lot of genetic complexity. The leukemic non-nodal MCL (nnMCL) is a less frequent subtype that originates from a cell with germinal center reaction. It is characterized by mutant IGHV genes, a lack of SOX11 expression, and minimal genetic changes. Every rearrangement results in a constant and excessive production of cyclin D1 protein. Approximately 5% of MCL cases do not exhibit CCND1 overexpression and rearrangement. They exhibit alternative primary rearrangements involving the CCND2 or CCND3. These rearrangements occur more often with IG light chains than with IGH. Somatic mutations in MCL differ according to the specific molecular subtype. cMCL has a lot of changes in genes that control the cell cycle, the response to DNA damage, epigenetic modification, the NOTCH pathway, and NF-kB signaling pathways. Mutations in the TP53 gene and an elevated level of genomic complexity correlate with worse prognosis in both subtypes of MCL [33].

Mechanisms: Currently, various studies suggest the repetitive but less frequent gain of functional mutations in Notch1 and Notch2 as found in B-cell carcinomas, such as DLBCL, MCL, SMZL, CLL, and infrequently in FL. There is also the possibility of the existence of nonmutational Notch initiation mechanisms [56]. Some data also suggest the participation of Hedgehog signaling in the survival or proliferation of cancerous stem cells in certain hematopoietic malignancies, including acute leukemias, chronic myelogenous leukemias, and plasma cell myeloma. The secretion of Hedgehog ligands occurs inside the stromal cells in a paracrine model that contributes to the initiation of Hedgehog signals in malignancies of low-grade B cells, such as MCL, CLL/SLL, and plasma cell myeloma [57].

3.6. MZLs

MZLs represent the second most common category of low-grade BCLs. The location of the affected area divides this entity into three subgroups: extranodal (EMZL) of MALT, splenic (SMZL), and nodal (NMZL).

MZL Genetics: These entities differ in their biological and genomic features; however, all subtypes share certain cytogenetic alterations, such as gains of chromosomes 3/3q and 18/18q. These changes occur in approximately 20%–30% and 20%–25% of instances, respectively. Numerous genetic factors frequently activate the NF-kB signaling pathway in MZL [33].

Mechanisms: 10 to 30 percent of the time, deletions, and/or somatic mutations are what turn off TNFAIP3, which is a negative regulator of NF-kB. Somatic mutations in SMZL and NMZL (3%–5%), primarily translocations in EMZL, can impact BIRC3, while somatic mutations in CARD11 (3%–7%) frequently affect it. All MZLs have somatic mutations in genes that control epigenetics. These genes are KMT2D, CREBBP, TBL1XR1, ARID1A, EP300, EZHZ, and TET2. Some entities have a larger concentration of specific mutated genes, such as KMT2D in NMZL, whereas EZH2 is essentially absent in SMZL [33].

In conclusion, various subtypes of B-NHL exhibit unique molecular and genetic alterations that markedly affect their pathogenesis, clinical behavior, and therapeutic responses. Customizing treatment according to these molecular characteristics enhances disease management and improves patient outcomes. The molecular subtype of DLBCL influences treatment response and prognosis. Standard therapies demonstrate reduced efficacy in ABC-type DLBCL compared to GCB-type DLBCL. The aggressive characteristics of MCL and CLL, which can evolve into a more severe form, frequently necessitate intensive treatment protocols, including high-dose chemotherapy and targeted therapies such as BTK inhibitors (e.g., ibrutinib). The treatment response may present challenges, and relapse of the disease is frequently observed. The following section will provide an overview of targeted therapies that are presently utilized in clinical settings, as well as those under development for BCLs.

4.1. Targeting the BCR Signaling Pathway

BTK-driven pathways play a big role in the survival of cancerous B cells and the growth of tumors in different types of NHL, even when they are not activated normally [58]. A BTK inhibitor is a novel pharmacological agent demonstrating potential effectiveness in BCLs. Turning on BTK initiates downstream signaling pathways that drive cell division, growth, survival, motility, cytokine production, and antigen presentation. The direct downstream transfer of signals from BCR to BTK makes it an attractive target for inhibition through precise pharmacological design. The Food and Drug Administration (FDA) has authorized the use of two oral BTK inhibitors, ibrutinib, acalabrutinib, and zanubrutinib, to date now (Table 2) [59].

4.2. Targeting the PI3K–AKT–mTOR Pathway Inhibitors

The PI3K pathway is crucial to cell survival, proliferation, and differentiation. Thus, PI3K is a major therapeutic target for various human malignancies, including B-NHLs. Four isoforms of P13K catalytic domains exist: p110α, p110β, p110γ, and p110δ. Many tissues use different signaling pathways for each isoform. Among all isoforms, the p110δ isoform is dominant in lymphoid cells and is important for B-NHL signaling. The US FDA approved idelalisib, duvelisib, and copanlisib as PI3K inhibitors. Clinically, PI3K isoform overexpression predicts poor survival. The overactive PI3K signaling pathway in B-cell neoplasms makes chemotherapy less effective, which makes it a good target for treatment.

4.3. BCL2 Inhibitors in Apoptosis Pathway

Apoptosis is initiated more rapidly in the intrinsic apoptotic pathways because of hypoxia, DNA damage, and oncogenic stress. The control and transduction of the signals in this type of pathway are done by the interaction of BCL2 family members, DNA checkpoint proteins, and p53, which are situated in the downstream as well as upstream cascades. This finally helps in the activation of caspase 3 and caspase 7 for producing extrinsic pathway-like effects [25]. Recently, “high-grade BCL with MYC and BCL2 and/or BCL6 rearrangements” (HGBL-DH) was officially classified as a distinct entity by the WHO. Numerous cancer centers recommend dose-intensive chemotherapy regimens due to the extremely poor prognosis associated with these lymphomas [50]. The development of an inhibitor of BCL2 is considered an optimal target for therapeutic development of malignant lymphomas.

4.4. The NF-κB Signaling Pathway Target Remedies

For the past 30 years, academia and the pharmaceutical industry have concentrated on targeting the key components of the NF-κB signaling pathway. This extensive research initiative has resulted in the creation of multiple therapeutic strategies capable of modulating the NF-κB core pathway [120].

4.5. Other Pathways and Novel Approaches

Blocking the Notch pathway can either directly or indirectly affect the cancerous cells. It suppresses the tumor growth by decreasing the supply of blood to the cancerous cells as a result of angiogenesis dysregulation and by disrupting tumor-forming stem cells. This became the basis for the therapeutic approaches used in cancer-inhibiting strategies. Also, it is a well-known fact that tumor cells sometimes go through many mutational processes in various cascades interconnected with Notch (WNT and Hedgehog), which suggest the usage of target-based remedies when administered in combined form. Combining Notch inhibitors with traditional chemoradiotherapy is also found to be effective because of the enhanced curative effect when administered in combined form. Many Notch-targeting strategies, such as inhibitors of α-secretase (ASIs) and γ-secretase (GSIs), immunotherapeutic agents along with neutralizing antibodies that target either ligands or Notch receptors, and using soluble recombinant receptors and ligands as traps are currently under development [123].