Molecular Mechanisms of Diffuse Large B-Cell Lymphoma and the Complexities of Tumor Development

Summary

Diffuse large B-cell lymphoma (DLBCL), the most prevalent aggressive non-Hodgkin lymphoma, exhibits substantial molecular heterogeneity and arises from germinal center or post-germinal center B cells through recurrent genetic and epigenetic dysregulation of critical signaling pathways. Aberrations involving BCL6, MYC, MYD88, and components of B cell receptor and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling play central roles in lymphomagenesis, treatment resistance, and clinical outcomes. Gene expression profiling has defined major molecular subgroups in DLBCL, including germinal center B cell–like and activated B cell–like tumors, that show distinct pathogenesis and prognosis. High-risk entities, such as double- and triple-hit lymphomas, remain therapeutically challenging despite advances in immunochemotherapy. Recent progress in molecular diagnostics and targeted therapies, including immune checkpoint inhibition, Bruton tyrosine kinase inhibitors, B-cell lymphoma 2 (BCL2) antagonists, and Chimeric antigen receptor-T cells, has expanded precision-based treatment strategies. This review summarizes advances in understanding the molecular mechanisms of DLBCL and emphasizes emerging therapeutic approaches informed by genomic and microenvironmental discoveries.

Introduction

Diffuse large B-cell lymphoma (DLBCL) represents the most diagnosed aggressive lymphoma among adults, comprising approximately one-third of non-Hodgkin lymphoma cases worldwide [1]. This malignancy primarily affects adults, shows a slight male predominance, and is marked by the rapid expansion of atypically large B cells that infiltrate the lymphoid tissue in a diffuse pattern rather than forming well-defined clusters [1]. This disruption in growth reflects the high-grade nature of the disease and underscores the urgency of diagnosing the disease early and developing better therapeutic strategies [1,2].

Clinically, patients most often present with rapidly enlarging lymphadenopathy, while extranodal involvement is observed in a substantial proportion of cases. Diagnostic evaluation relies on excisional lymph node biopsy with immunohistochemical confirmation of B cell lineage, supplemented by molecular techniques such as gene expression profiling and fluorescence in situ to identify clinically relevant genetic abnormalities and biologically distinct subgroups [3,4]. Advanced staging can be performed using positron emission tomography/computed tomography to assess nodal and extranodal involvement [5].

Molecular profiling has established 2 main biological DLBCL subgroups: germinal center B cell–like (GCB) and activated B cell–like (ABC), which arise from distinct cells of origin, exhibit distinct oncogenic signaling pathways, and differ in clinical behavior [6]. The ABC DLBCL is frequently driven by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mediated signaling and sustained B cell receptor activation, features associated with inferior outcomes, whereas GCB DLBCL commonly exhibits epigenetic dysregulation and a comparatively favorable prognosis [2]. Beyond tumor-intrinsic alterations, the tumor microenvironment contributes significantly to disease progression, immune evasion, and therapeutic resistance [7]. Integration of genomic, epigenomic, and microenvironmental data has refined risk stratification and continues to inform the development of targeted and precision-based therapeutic strategies [8,9].

Literature search

For this narrative review, relevant literature was retrieved from PubMed/MEDLINE, Embase, and Web of Science, with a focus on studies addressing the molecular basis of diffuse large B-cell lymphoma. Relevant peer-reviewed original studies and review articles addressing genetic alterations, signaling pathways, tumor microenvironment, and targeted therapies in DLBCL were considered. The selected literature was evaluated qualitatively to provide an integrated overview of current molecular insights rather than a systematic assessment.

Cell of origin in DLBCL

Most DLBCLs arise from B lymphocytes that reside within the germinal centers of secondary lymphoid organs, which serve as specialized microanatomical sites for the generation of high-affinity antibody responses [10]. Upon stimulation by T cell-dependent antigens, naïve B cells migrate to these lymphoid structures and undergo clonal expansion. This process leads to the formation of 2 functionally distinct zones within the germinal center: the dark zone and the light zone. In the dark zone, centroblasts proliferate extensively and experience somatic hypermutation (SHM), a tightly regulated process that generates point changes in immunoglobulin genes to enhance antibody affinity [11,12,13].

The SHM is driven by activation-induced cytidine deaminase (AID), which alters cytosine bases and promotes the activation of error-prone deoxyribonucleic acid (DNA) repair pathways. Although this mechanism is essential for antibody diversification, it is inherently mutagenic and may inadvertently affect non-immunoglobulin loci, including oncogenes and tumor suppressor genes [14,15]. Such off-target effects contribute to genomic instability and create a permissive environment for lymphomagenesis.

B-cell lymphoma 6 (BCL6) plays a central regulatory role within germinal centers by maintaining the proliferative and undifferentiated state of centroblasts [16]. This transcriptional repressor suppresses genes regulating cell-cycle checkpoints, DNA damage signaling, and cellular maturation, thereby allowing rapid cell division during SHM without triggering apoptosis. Physiological germinal center maturation requires subsequent downregulation of BCL6 in the light zone, a process mediated by follicular helper T-cell interactions and B cell receptor signaling. This transition allows selected B cells differentiate into plasma cells or memory B cells. Disruption of these tightly controlled regulatory events increases susceptibility to malignant transformation [17].

The DLBCL most commonly arises from germinal center or post–germinal center B cells following SHM or class switching recombination (CSR), distinguishing it from other B cell malignancies, such as mantle cell lymphoma or lymphoblastic lymphoma [18,19]. These lymphomas frequently harbor mutations and rearrangements driven by processes such as SHM and CSR, which typically enhance antibody responses. Studies in mice demonstrated that AID is required for the formation of germinal center (GC)-related lymphomas. Therefore, under specific pathogenic conditions, pathways crucial for GC immunity may also cause lymphoma [11].

Pathophysiology and molecular subgroups of DLBCL

A wide range of intricate genetic alterations and molecular anomalies that impair normal B cell growth and function are the pathophysiological drivers of DLBCL. The CSR of B cells occurs in GCs of secondary lymphoid tissues, where most DLBCLs are produced by B cells at different phases of maturity. B cells undergo CSR and SHM to produce high-affinity antibodies [20]. Transcription factors, including myelocytoma (MYC), which support cell cycle progression, and BCL6, which stimulates cell proliferation and inhibits differentiation, carefully regulate these processes.

However, these regulatory systems are dysregulated in DLBCL [2]. Alterations affecting genes including BLC6 and MYC can drive unchecked B cell survival and proliferation, thereby promoting lymphomagenesis. In particular, aggressive clinical behavior and poor prognosis are caused by MYC dysregulation, which frequently occurs in conjunction with BCL2 overexpression, as observed in “double-hit” lymphomas [21].

Furthermore, aberrant activation of the B cell receptor (BCR) signaling represents a central pathogenic mechanism in DLBCL. Mutations affecting components of the BCR signaling complex, such as CD79A and CD79B, result in chronic activation of downstream pathways, including NF-κB and phosphatidylinositol 3-kinase (PI3K)– protein kinase B (AKT)– mammalian target of rapamycin (mTOR), enabling antigen-independent survival and proliferation [22,23]. The ABC subclass commonly harbors MYD88 mutations, most notably L265P, which further amplify NF-κB signaling and are associated with worse clinical outcomes [24]. Other mutations that often affect differentiation, apoptosis, and epigenetic regulation include mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2), cyclic amp-responsive element-binding protein (CREBBP), E1A binding protein P300 (EP300), and Notch pathway members.

The DLBCL is categorized into GCB and ABC molecular subgroups according to gene expression profiles. The GCB-DLBCL derives from centroblasts within the germinal center and is generally associated with more favorable outcomes [25,26]. This subtype commonly exhibits alterations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) and phosphatase and tensin homolog (PTEN), as well as chromosomal rearrangements such as translocations (t)(14;18), resulting in BCL2 overexpression. Cases with concurrent MYC and BCL2 abnormalities, which confer a more aggressive clinical course, may also fall within this category [25,27,28]. In contrast, ABC-DLBCL originates from post–germinal center B cells and is characterized by persistent NF-κB activation due to mutations in myeloid differentiation primary response 88 (MYD88), cluster of differentiation 79B (CD79B), or caspase recruitment domain family member 11 (CARD11) [27,29]. These changes reduce susceptibility to traditional treatments, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), and increase resistance to apoptosis. Recent advances in genomic and transcriptomic analyses have enabled more accurate DLBCL subclassification beyond the GCB and ABC frameworks.

Distinct genetic subgroups have been identified, including NOTCH2 mutations and BCL6 rearrangements (BN2), EZH2 mutations with BCL2 translocations (EZB), NOTCH1 mutations (N1), and coexisting MYD88 and CD79B mutations (MCD) [28]. These molecular clusters demonstrate distinct biological behaviors, prognostic implications, and therapeutic vulnerabilities. Targeted approaches, such as Bruton's tyrosine kinase (BTK) inhibitors that disrupt chronic BCR signaling and immunomodulatory agents like lenalidomide that attenuate NF-κB activity, have shown particular promise in ABC-DLBCL [6,29]. Overall, the pathobiology of DLBCL is defined by molecular events such as aberrant expression networks that alter B cell differentiation and survival processes. Specific signaling pathways and genetic alterations are associated with tumor development. Molecular classification not only improves prognostic prediction but also provides new treatment strategies and prospects for successful subsequent therapy in patients with DLBCL. GCB-DLBCL is more commonly linked to t(14;18), EZH2 mutations, and MYC–BCL2 double-hit features, whereas ABC-DLBCL is dominated by a constitutively activated NF-κB pathway and BCL2 amplification [30].

Molecular mechanisms and genetic mutations of DLBCL

The development of DLBCL involves the accumulation of various genetic mutations that affect tumor suppressor genes, proto-oncogenes, and other critical molecular components. As in most cancers, oncogenic deregulation in DLBCL arises from mechanisms such as point mutations, gene or copy number variations, and 2 specific forms of genetic damage associated with physiological immunoglobulin gene modification in B cells. Genetic lesions related to AID activity may include errors during antigen receptor gene assembly, class-switch–associated damage, chromosomal rearrangements, and off-target hypermutation. Eliminating AID, an enzyme required for SHM and CSR, prevents MYC– immunoglobulin heavy-chain (IGH) translocation and the development of GC-derived lymphomas in mice. Chromosomal translocations in DLBCL do not typically result in the formation of fusion proteins. Instead, they often involve the juxtaposition of immunoglobulin (IG) locus enhancers with proto-oncogenes, such as BCL2, MYC, or BCL6. This misalignment leads to deregulated expression of these genes. Proto-oncogenes, normally subject to strict regulation in precursor cells, can become aberrantly activated in lymphoma cells (such as BCL6 translocations). Simultaneously, genes including BCL2 and MYC, typically absent from most GC B cells and not expressed in precursor cells, may be ectopically activated. The SHM is a genetic mechanism that induces mutations within the 5 regions of generally stable loci in GC B cells. In contrast to the tightly regulated SHM process, SHM induces mutations across multiple non-immunoglobulin genomic loci, affecting proto-oncogenes such as MYC and Proto-oncogene serine/threonine-protein kinase (PIM1). Pasqualucci et al. [31] reported that aberrant mutation patterns are characterized by biallelic mutations, multiple mutations within the same allele, and a strong resemblance to the SHM process, including the preferential targeting of specific DNA motifs. Both coding and non-coding regions exhibited these alterations. According to a recent study, chromosomal translocations and SHM are not randomly distributed; instead, they cluster within regulatory regions or super-enhancers, where sense and antisense transcription converge. Therefore, these regions are important AID-recruiting mediators. Advancements in sequencing technologies have revealed a high level of complexity in the DLBCL genome [26,31].

A significant percentage of the genome, particularly the non-coding regions, remains poorly understood, and these results likely underestimate the mutation burden. Mutations have been identified in putative mutable regions, indicating that these regions play essential regulatory functions in DLBCL [32]. Approximately 85% of all DLBCL cases exhibit these changes, highlighting the role of epigenetic modifications in lymphomagenesis. Mutations in these genes can affect immunological signaling, cell migration, apoptosis, and critical regulatory functions [33]. As epigenetic modifications can be reversed, they may be targets of therapeutic interventions, especially for patients whose tumors rely on certain epigenetic modifications. Substantial patient-to-patient variation in 70+ genetic lesions affects coding regions across DLBCL samples. These lesions contained mutations and number variations.

Approximately 150 essential driver genes in DLBCL have been identified in current investigations based on mutation incidence and recurrence [7,34,35]. A high number of mutated genes creates numerous opportunities for cooperative interactions between genetic lesions and cellular pathways in each case; the implications of these interactions are still unclear [21,35]. Numerous recurrent mutations occur in genes encoding histone and chromatin regulators, alongside additional mutations in other protein-coding regions. These include histones, methyltransferases, and acetyltransferases. Certain modifiers, such as AT-rich interaction domain 1A (ARID1A) and tet methylcytosine dioxygenase 2 (TET2), are also implicated in low-frequency mutations [7,21,35].

Histone-lysine N-methyltransferase 2D (KMT2D) also known as mixed lineage leukemia 2 is involved in histone modification and has an important role in regulating chromatin structure. In DLBCL, alterations in KMT2D are frequently reported and represent one of the most commonly observed genetic changes in this disease [26].

Inactivation of CREBBP and EP300

The GCB-DLBCL subtype, which represents approximately one-third of DLBCL cases, frequently harbors deletions or functional inactivation mutations of the histone acetyltransferase genes CREBBP and EP300 [36]. Both genes are essential regulators of transcription through their ability to acetylate histones and non-histone substrates, including the tumor suppressor p53. Histone acetylation promotes a permissive chromatin state that facilitates gene transcription, while acetylation of p53 enhances its transcriptional activity and pro-apoptotic function [28,37]. Loss-of-function alterations in CREBBP or EP300 lead to impaired acetylation, resulting in widespread transcriptional dysregulation. This includes reduced antigen presentation and attenuation of p53-dependent tumor suppressive responses, thereby promoting lymphomagenesis. These alterations are typically heterozygous, supporting a haploinsufficiency model in which loss of a single functional allele is sufficient to drive oncogenic transformation. Experimental evidence from murine models further supports this concept, as selective loss of CREBBP in GCB cells promotes lymphoma progression and dissemination, confirming its role as a tumor suppressor. Mutations affecting CREBBP and EP300 have also been associated with epigenetic repression of genes involved in immune surveillance, including those regulating class II transactivator expression and major histocompatibility complex class II molecules. This repression may impair immune recognition and facilitate immune evasion, contributing to disease progression. In addition to CREBBP and EP300, the transcription factor Forkhead box protein O1 (FOXO1) represents another key molecular regulator implicated in the pathogenesis of GCB-DLBCL [38]. The FOXO1 plays a critical role in maintaining germinal center architecture and B cell development by cooperating with BCL6 to sustain dark-zone–specific transcriptional programs.

The FOXO1 is controlled by the PI3K–AKT–mTOR signaling axis and is preferentially maintained in the germinal center dark zone, where low PI3K signaling preserves its nuclear localization and function. Disruption of this regulatory balance promotes aberrant B cell proliferation and malignant transformation via interactions with additional oncogenic pathways [39]. Between 8% and 10% of patients with DLBCL harbor FOXO1 mutations, which frequently involve residues required for AKT-mediated phosphorylation and cytoplasmic translocation [40]. These mutations result in persistent FOXO1 activity, aberrant germinal center dynamics, and promotion of lymphomagenesis. Although FOXO1 alterations are particularly enriched in relapsed or refractory GCB-DLBCL, where they may occur in up to 36% of cases, their precise prognostic and therapeutic implications remain incompletely defined and warrant further investigation [26,41].

Tumor microenvironment and key therapeutic targets in DLBCL progression

The tumor microenvironment (TME) in DLBCL represents a highly dynamic network composed of immune cells, stromal elements, and interconnected signaling pathways that collectively influence tumor progression, immune escape, and therapeutic resistance. Cytokine and chemokine signaling within the TME can exert dual effects, either promoting antitumor immune responses or facilitating lymphoma cell survival and progression. The molecular landscape of DLBCL integrates genetic subtypes, oncogenic signaling pathways, and microenvironmental interactions, collectively shaping disease behavior and therapeutic responsiveness, as illustrated in Fig. 1. Immune cells that interact with stromal and endothelial cells, including dendritic cells, macrophages, and regulatory T cells (Tregs), shape the TME to either support or suppress tumor growth [41]. In many cases, DLBCL cells evade immune detection through upregulation of immune checkpoint pathways, such as programmed cell death (PD)-1/programmed cell death-ligand (PD-L)1, and impairment of antigen presentation, thereby facilitating immune escape and disease progression. Key intracellular signaling cascades further contribute to these interactions. Activation of the PI3K–AKT–mTOR pathway enhances lymphoma cell growth and survival, whereas dysregulated Janus kinases (JAK)/signal transducer and activator of transcription proteins (STAT) signaling alters cytokine-mediated communication within the TME and supports tumor development [42]. The DLBCL is also associated with the Wingless-related integration site (Wnt)/β-catenin pathway; however, its precise function remains unclear. Rituximab, which targets cluster of differentiation 20 (CD20), is used in combination with CHOP chemotherapy. Recent methods have focused on the molecular weaknesses. More recently, treatment approaches have increasingly focused on exploiting molecular and immunological vulnerabilities.

Fig. 1.

Integrated framework of DLBCL. EZB: EZH2 mutations with BCL2 translocations, MCD: MYD88/CD79B subtype, BN2: BCL6/NOTCH2 subtype, N1: NOTCH1 subtype, BCR: B cell receptor, NF-KB: nuclear factor-kappa B, PI3K-AKT-mTOR: phosphatidylinositol 3-kinase - protein kinase B - mammalian target of rapamycin, p53: tumor protein, PD- 1/PD-L1: programmed cell death/programmed cell death ligand 1, BTK: bruton tyrosine kinase, BCL2: B-cell lymphoma 2, EZH2: enhancer of zeste homolog 2, CAR-T: chimeric antigen receptor T.

Chimeric antigen receptor (CAR)-T cell therapy uses a patient's own immune cells to eliminate malignant B cells, whereas BTK inhibitors, such as ibrutinib, inhibit persistent BCR signaling. In addition, epigenetic treatments, including histone deacetylase and DNA methyltransferase inhibitors, have shown clinical benefit in selected patient groups. However, despite these advances, disease relapse remains common, underscoring the need for rational combination strategies, improved patient selection, and prospective validation of predictive biomarkers [42,43,44].

Schematic overview illustrating major genetic subtypes, oncogenic signaling pathways, epigenetic alterations, tumor microenvironment interactions, and therapeutic strategies. Abbreviations are defined in the text.

The DLBCL is a clinically aggressive type of non-Hodgkin lymphoma with substantial biological heterogeneity driven by dysregulated DNA repair, aberrant signaling pathways, and cumulative genetic and epigenetic alterations [2]. The GCB-DLBCL and ABC-DLBCL are the 2 main molecular subtypes of DLBCL defined by genomic profiling, and each subtype has unique genetic and signaling features [45]. Frequent chromosomal translocations, such as translocation (t)(14;18), are associated with the GCB subtype and promote cell survival by overexpressing BCL2 [2,46]. In addition, activating mutations in EZH2 promote inappropriate silencing of tumor suppressor genes through altered histone methylation, further contributing to malignant transformation [47].

In contrast, ABC-DLBCL is predominantly dependent on persistent activation of the NF-κB signaling pathway through recurrent mutations in MYD88, CARD11, and components of the BCR complex, including CD79A and CD79B [48,49]. The MYD88 L265P mutation, present in approximately 40% of ABC-DLBCL cases, induces persistent Toll-like receptor signaling and downstream activation of Interleukin-1 receptor-related kinase 1/4 resulting in sustained NF-κB and interferon-regulatory factor-mediated transcriptional programs that promote cell survival and resistance to apoptosis [24,50]. Mutations in CD79A or CD79B further amplify spleen tyrosine kinase and BTK signaling, reinforcing chronic BCR-dependent NF-κB activation [51,52]. Alterations in tumor suppressor pathways, particularly tumor protein (TP)53, occur in a clinically relevant subset of DLBCL and are strongly associated with chemoresistance and poorer survival outcomes [53]. Additional disruptions in cell-cycle regulation arise from cyclin-dependent kinase inhibitor 2A (CDKN2A) inactivation, leading to loss of p16INK4a function and unchecked progression through the retinoblastoma tumor suppressor protein (Rb)/E2F axis [26,54].

Epigenetic dysregulation represents another fundamental mechanism in DLBCL pathogenesis. Recurrent alterations in CREBBP and EP300 impair histone acetylation and suppress transcription of immune-related genes, thereby facilitating immune evasion and lymphoma progression [55]. Aberrant PI3K–AKT–mTOR signaling further enhances tumor growth and survival often through loss of PTEN function or activating mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [56]. Dysregulated JAK/STAT signaling, driven by mutations in suppressor of cytokine signaling 1 (SOCS1) or STAT3, contributes to cytokine-dependent proliferation and immune escape, particularly in GCB-DLBCL [26]. In this context, PI3K inhibitors, including idelalisib and duvelisib, have shown substantial therapeutic potential [56].

The transcriptional repressor BCL6, a key regulator of GC formation and maintenance, is commonly deregulated in both GCB and ABC subtypes, leading to impaired differentiation and sustained proliferation [16]. Apoptotic resistance in DLBCL is further reinforced by dysregulation of BCL2 family proteins. The BCL2 overexpression, frequently mediated by t(14;18), contributes to resistance against chemotherapy-induced cell death [57]. Targeting this pathway with venetoclax, a selective BCL2 inhibitor, has demonstrated clinical activity both as monotherapy and in combination regimens [58,59].

Beyond tumor-intrinsic alterations, the immune microenvironment is a key driver of DLBCL progression. Tumor-associated macrophages and regulatory T cells contribute to an immunosuppressive niche that promotes lymphoma growth [41]. Immune evasion mechanisms include PD-L1 overexpression and amplification of the 9p24.1 locus, rendering immune checkpoint blockade with agents such as pembrolizumab a viable therapeutic strategy in selected patients [60,61].

Recent advances in multi-omics profiling and next-generation sequencing have further refined the understanding of DLBCL heterogeneity. Novel genetic clusters—including EZB (EZH2), N1 (NOTCH1), MCD (MYD88/CD79B), and BN2 (BCL6 fusions)—extend beyond the traditional GCB/ABC framework and highlight the need for personalized treatment approaches [26]. Integration of genomic alterations with immune microenvironment signatures has demonstrated prognostic value and predictive relevance for treatment response [7,8,41]. Collectively, these findings support the rational combination of targeted agents such as BTK, PI3K, and BCL2 inhibitors with immune-based therapies in biomarker-selected patient populations. Table 1 summarizes the studies on the molecular mechanisms of DLBCL.

Table 1.

Representative landmark studies regarding DLBCL's mechanism, classification, and therapeutic targeting.

Author	Study type	Cohort/model	Key DLBCL contribution	References
Schmitz et al.	Genomic classification	574 human DLBCL	Introduced EZB, MCD, BN2, N1 genetic clusters with prognostic impact.	[2]
Wright et al.	Computational classifier	~2,000 multi-cohort	Probabilistic tool assigning genetic subtypes with therapeutic relevance.	[26]
Xu-Monette et al.	Clinicogenomic	>300 human DLBCL	TP53 mutation profiling linked to adverse outcomes under R-CHOP.	[53]
Cerchietti	Translational	Human DLBCL	Genetic mechanisms shaping the tumor microenvironment composition.	[7]
Koumpis et al.	Immune-microenvironment review	Multi-dataset DLBCL	Linked immune signatures to prognosis and immunotherapy implications.	[41]
Zhang et al.	Multi-omics	>100 human DLBCL	Integrated multi-omics for diagnosis and treatment-response prediction.	[8]

DLBCL: diffuse large B-cell lymphoma, GCB: germinal center B-cell–like, ABC: activated B-cell–like, EZB: EZH2/BCL2 subtype, MCD: MYD88/CD79B subtype, BN2: BCL6/NOTCH2 subtype, N1: NOTCH1 subtype, R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, TP53: tumor suppressor gene.

In conclusion, diffuse large B-cell lymphoma represents a biologically diverse B cell malignancy arising from germinal center and post–germinal center B cell lineages. Integration of cell-of-origin classification with emerging genetic cluster frameworks has improved insight into disease biology and supports the advancement of precision-based therapeutic strategies. Physiological processes such as class-switch recombination and somatic hypermutation promote lymphomagenesis by generating genetic changes that affect key regulatory genes, including BCL6, MYC, and MYD88, thereby disrupting normal B cell differentiation and survival. As the disease evolves, dysregulation within oncogenic pathways, including NF-κB and PI3K/AKT/mTOR, becomes increasingly prominent.

Although many patients benefit from standard immunochemotherapy, outcomes remain suboptimal in high-risk and relapsed or refractory disease. The advent of targeted therapies—including BCL2 antagonists, BTK inhibitors, epigenetic modulators, CAR-T cell therapy, and immune checkpoint inhibitors—has expanded treatment options and demonstrated encouraging clinical activity. Future research should focus on integrating genetic clusters (EZB, MCD, BN2, and N1) with immune and stromal microenvironment profiles to improve prediction of treatment response and long-term outcomes. Evaluation of rational combination strategies, along with standardized genomic classifiers such as those described by Wright et al., may facilitate translation of molecular discoveries into routine clinical practice and further advance personalized management of DLBCL [26].

Acknowledgement

The author gratefully acknowledges Editage Editing Services (www.editage.com) for the English language editing.

Disclosure

The author declares no conflict of interest and received no specific funding for this study. The author takes full responsibility for the content of the manuscript, and Grammarly was used for language editing only.