Pathogenesis Of B-cell non-Hodgkin Lymphoma Research Articles

Analysis of hepatitis B virus infection in 1424 patients with different pathological types of lymphoma (2018-2022): A real-world, retrospective study.

Recent studies have found a high prevalence of hepatitis B virus (HBV) infection in patients with non-Hodgkin's lymphoma (NHL), especially B-cell non-Hodgkin's lymphoma (B-NHL). However, most studies did not classify it and analyze the correlation between HBV and its various subtypes. The authors retrospectively analyzed 1424 patients with lymphoma. Differences in the prevalence of HBV infection in patients with different pathological types of lymphoma were analyzed. The clinical characteristics, progression-free survival (PFS), and overall survival (OS) of HBV-positive and negative B-NHL subtypes were compared according to HBV infection. The HBV infection rate in NHL patients was 7.65%, which was higher than that in HL patients (2.59%, p < 0.05). The HBV infection rate in the B-NHL was higher than that in the T-cell non-Hodgkin's lymphoma (T-NHL) (8.14% vs. 4.95%). The HBV infection rate in the aggressive B-NHL was similar to that of the indolent B-NHL (8.30% vs. 7.88%), and the highest HBV infection rates were found in diffuse large B-cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, but no significant differences in clinical characteristics, PFS, and OS were seen between HBV-positive and negative patients in the two subtypes. There was an association between HBV infection and the development of NHL and HBV infection may play a role in the pathogenesis of B-NHL, but not T-NHL.

Association between CHFR and PARP-1, and Their Roles in Regulation of Proliferation and Apoptosis of B Cell Lymphoma

Background. Aberrant methylation of checkpoint with forkhead and ring finger domains (CHFR) was found in B-cell non-Hodgkin lymphoma (NHL), whereas its role in carcinogenesis is not clear. CHFR can control poly (ADP-ribose) polymerase levels by causing its degradation. The study was aimed to explore the roles and mechanisms of CHFR in the pathogenesis of B-cell NHL. Methods. Short hairpin ribonucleic acid (ShRNAs) targeting CHFR and poly (ADP-ribose) polymerase 1 (PARP-1) were transduced into Raji cells, and real-time polymerase chain reaction (PCR) and western blotting were carried out to determine their expression. Afterwards, the CCK-8 assay and flow cytometry were used to evaluate the cell growth and apoptosis. Tumor size and weight were determined using a xenograft model, and decitabine (5-Aza-dC) was used to further determine the methylation status of CHFR through a methylation specificity-PCR assay. Results. 5-Aza-dC-treatment promoted the expression of CHFR and decreased the expression of PARP-1 at both messenger ribonucleic acid (mRNA) and protein levels. 5-Aza-dC also accelerated Raji-cell apoptosis and restrained its growth in vitro and in vivo ( P &lt; 0.05 ). These results were contrary to those observed in the shRNA-CHFR group but consistent with those observed in the shRNA-PARP-1 group. The expression profiles of CHFR and PARP-1 in the xenograft model were consistent with those in the cellular model. Treatment with 5-Aza-dC led to demethylation of CHFR in nude mice. Besides, there may be a negative correlation between CHFR and PARP-1 in B-cell NHL cells. Conclusion. Our findings indicated that 5-Aza-dC could lead to the demethylation of the CHFR promoter and suppress Raji cell growth.

No increased risk of mature B-cell non-Hodgkin lymphoma after Q fever detected: results from a 16-year ecological analysis of the Dutch population incorporating the 2007-2010 Q fever outbreak.

BackgroundA causative role of Coxiella burnetii (the causative agent of Q fever) in the pathogenesis of B-cell non-Hodgkin lymphoma (NHL) has been suggested, although supporting studies show conflicting evidence. We assessed whether this association is present by performing a detailed analysis on the risk of mature B-cell NHL after Q fever during and after the largest Q fever outbreak reported worldwide in the entire Dutch population over a 16-year period.MethodsWe performed an ecological analysis. The incidence of mature B-cell NHL in the entire Dutch population from 2002 until 2017 was studied and modelled with reported acute Q fever cases as the determinant. The adjusted relative risk of NHL after acute Q fever as the primary outcome measure was calculated using a Poisson regression.ResultsBetween January 2002 and December 2017, 266 050 745 person-years were observed, with 61 424 diagnosed with mature B-cell NHL. In total, 4310 persons were diagnosed with acute Q fever, with the highest incidence in 2009. The adjusted relative risk of NHL after acute Q fever was 1.02 (95% CI 0.97–1.06, P = 0.49) and 0.98 (95% CI 0.89–1.07, P = 0.60), 0.99 (95% CI 0.87–1.12, P = 0.85) and 0.98 (95% 0.88–1.08, P = 0.67) for subgroups of diffuse large B-cell lymphoma, follicular lymphoma or B-cell chronic lymphocytic leukaemia, respectively. Modelling with lag times (1–4 years) did not change interpretation.ConclusionWe found no evidence for an association between C. burnetii and NHL after studying the risk of mature B-cell NHL after a large Q fever outbreak in Netherlands.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Microsatellite Instability Is Rare in B-Cell Non-Hodgkin's Lymphomas

AbstractMicrosatellite instability (MSI), a symptom of defect in DNA mismatch repair function, represents a type of genomic instability frequently detected in many types of cancers. However, the involvement of MSI in non-Hodgkin's lymphomas (NHL) has not been conclusively investigated. In this study, we have tested the presence of MSI in 69 cases of B-cell NHL (B-NHL) representative of the various histologic categories of the disease and including 17 cases of acquired immunodeficiency syndrome (AIDS)-related B-NHL (AIDS-NHL). In addition, for selected B-NHL cases, consecutive samples obtained before and after clinical progression (with and without concomitant histologic transformation) were also investigated. Five distinct microsatellite repeats (2 dinucleotide, 2 trinucleotide, and 1 tetranucleotide repeats) were analyzed by polymerase chain reaction in all cases. MSI, defined by the presence of microsatellite alterations in two or more of the five microsatellite loci tested, was not found in NHL. In contrast to a previous study reporting the frequent association between MSI and AIDS-NHL, we found this abnormality in only 1 of 17 cases of AIDS-NHL representative of the major subtypes. Overall, these data indicate that defects in DNA mismatch repair do not contribute significantly to the molecular pathogenesis of B-NHL.

Exome Sequencing of Hodgkin's and Non-Hodgkin Composite Lymphomas Identifies Shared Somatic Mutations Indicative of Common Founding Precursors

Background: Composite lymphomas (CLs) describe the rare situation when two morphologically distinct lymphomas occur in the same patient. Prior studies have supported a shared origin of CLs based on shared chromosomal translocations and/or the presence of shared immunoglobulin rearrangements. We used exome sequencing to examine somatic events in two cases of CLs. We hypothesized that each lymphoma will have shared and unique mutations, consistent with the presence of a common lymphoma precursor. Further, we postulated that the shared mutations represent potential initiating events in lymphomagenesis. Finally, because each case includes a Hodgkin (HL) and non-Hodgkin lymphoma (NHL), we hypothesize that the somatic mutations found in HL may offer insight into genomic drivers of HL.Clinical Synopsis:Case 1 was a 57-year-old man who presented with abdominal pain associated with a small bowel obstruction (SBO) and lymphadenopathy (LAD). Pathology showed DLBCL (diffuse large B-cell lymphoma, non-germinal center subtype; stage IV). He was treated with 6 cycles of R-CHOP with complete response. Seven months after the completion of R-CHOP, he presented with left neck LAD. An excisional biopsy revealed classical HL (stage II). Hodgkin and Reed-Sternberg (HRS) cells comprised 10% of the sample. He was treated with 3 cycles of ABVD and involved-field radiation therapy. Case 2 was a 66-year-old man with a history of solitary LAD who presented with increasing LAD, night sweats, and a chest wall mass. An excisional biopsy revealed both follicular lymphoma (FL; grade I-II) and classical HL in distinct areas of the lymph node. HRS cells comprised 30% of the sample. FISH studies were positive for t(14;18). He was treated with ABVD for 6 cycles with partial response. Upon progression, a repeat lymph node biopsy showed persistent HL. He was treated with bendamustine and rituximab for 4 cycles with progressive disease.Methods: We performed whole exome sequencing on formalin fixed paraffin embedded tumor samples and matched normal skin samples. We used our standard somatic variant calling pipeline to call somatic variants. SNV (single nucleotide variant) and indel calls were filtered for basic quality metrics and, using in-house software, were processed through a Bayesian classifier to remove false positive somatic events. Filtered variants were manually reviewed to further verify somatic status. Somatic variants were validated using Ampliseq in Case 1.Results: Sequencing resulted in >90% of the target regions with at least 20x in all samples. The mean depth of the NHL and normal samples in Case 1 was >65x. To account for the low malignant tumor cellularity of HL, the HL sample of Case 1 was sequenced to a mean depth of 310x. The mean depth for all samples in Case 2 was >100x (FL = 188x; normal = 104x; HL = 215x). After filtering, we identified 60 and 133 variants in 57 and 101 genes in Case 1 and Case 2, respectively. In Case 1, we identified three sites inTP53, TNFRSF14, and RASAL2 that were shared. We also identified variants in HIST1H2AG, KMT2D, and STAT3 unique to the DLBCL sample, and two mutations in PTPRT unique to the HL sample of Case 1 (Figure 1). In Case 2, we identified shared variants in TNFRSF14 and HIST1H2BF. We also identified two distinct BCL10 mutations in the FL and HL samples of Case 2 (Figure 1).Conclusions: From the shared somatic mutations identified, we infer that a shared lymphoma precursor for each case is likely, and the shared mutations may be early initiating events. In both cases, a shared nonsense mutation was found at TNFRSF14. TNFRSF14 is recurrently mutated in NHL, and recurrent deletions involving TNFRSF14 have been described in HL. Further work is needed to understand how TNFRSF14 alterations drive HL vs. NHL. Finally, it is intriguing that the HL samples contain independent mutations in PTPRT and BCL10. PTPRT is a known cancer gene, and BCL10 has been shown to be associated with the pathogenesis of B-cell NHLs. These data provide new hypotheses for loci involved in HL pathogenesis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The molecular pathogenesis of B-cell non-Hodgkin lymphoma.

The B-cell non-Hodgkin lymphomas (B-NHL) are a diverse group of haematological malignancies which arise from the mature B-lymphocyte compartment. Recently, our understanding of the molecular pathogenesis of these disorders has greatly increased due to technological advances such as high-throughput DNA sequencing techniques. A paradigm of B-NHL pathogenesis has emerged where the normal genetic processes that are central to generating B-cell receptor diversity (somatic hypermutation and class switch/VDJ recombination) also drive the genesis of large-scale, chromosomal-level genetic lesions and smaller-scale gene-level mutations to produce the malignant phenotypes observed. Whilst a significant degree of genetic heterogeneity exists within each B-NHL subtype, the genetic lesions present within each subtype show a degree of convergence on common intracellular signalling, epigenetic and cell cycle pathways. This convergence gives an insight into the key oncogenic drivers of specific B-NHL subtypes and potential targets for therapeutic intervention. This review covers the current understanding of the causative genetic processes of B-NHL, the associated driving molecular lesions and the implications of these findings for the treatment of this group of disorders.

Malignant B Cells Induce the Conversion of CD4+CD25− T Cells to Regulatory T Cells in B-Cell Non-Hodgkin Lymphoma

Recent evidence has demonstrated that regulatory T cells (Treg) were enriched in the tumor sites of patients with B-cell non-Hodgkin lymphoma (NHL). However, the causes of enrichment and suppressive mechanisms need to be further elucidated. Here we demonstrated that CD4+CD25+FoxP3+CD127lo Treg were markedly increased and their phenotypes were different in peripheral blood (PB) as well as bone marrow (BM) from newly diagnosed patients with B-cell NHL compared with those from healthy volunteers (HVs). Involved lymphatic tissues also showed higher frequencies of Treg than benign lymph nodes. Moreover, the frequencies of Treg were significantly higher in involved lymphatic tissues than those from PB as well as BM in the same patients. Suppression mediated by CD4+CD25+ Treg co-cultured with allogeneic CFSE-labeled CD4+CD25− responder cells was also higher in involved lymphatic tissues from B-cell NHL than that mediated by Treg from HVs. In addition, we found that malignant B cells significantly induced FoxP3 expression and regulatory function in CD4+CD25− T cells in vitro. In contrast, normal B cells could not induce the conversion of CD4+CD25− T cells to Treg. We also showed that the PD-1/B7-H1 pathway might play an important role in Treg induction. Taken together, our results suggest that malignant B cells induce the conversion of CD4+CD25− T cells to Treg, which may play a role in the pathogenesis of B-cell NHL and represent a promising therapeutic target.

Genome-Wide Analysis of B Cell Non-Hodgkin's Lymphoma Disclosed Frequent Involvement of Genes in NFkB Pathway

B cell non-Hodgkin's lymphoma (B-NHL) consists of different pathological entities that are frequently characterized by distinct genetic alterations. However, the knowledge on these genetic lesions in B-NHL is still limited. In order to obtain a more comprehensive view of genetic lesions in B-NHL, we performed genome-wide analysis of copy number (CN) alterations as well as allelic imbalances using Affymetrix SNP arrays in 190 B-NHL cases, including 64 samples of diffuse large B-cell lymphoma (DLBCL), 62 of follicular lymphoma (FL), 64 of mucosa-associated lymphoid tissue lymphoma (MALT-L). SNP array data were analyzed with CNAG/AsCNAR software, which enabled sensitive detection of CN alterations in allele-specific manner, and thus allelic imbalances, without depending on availability of paired normal controls. Most frequent numerical abnormalities in B-NHL were gains of chromosomes 3 and 18, although gains of chromosome 3 were less prominent in FL. Chromosomal deletions that lead to loss of heterozygosity (LOH) were commonly found in 1p, 6q and 10q. However, the more chracteristic feature of B-NHL genomes was high frequency of CN netural LOH or uniparental disomy (UPD), which was found in 35 cases of DLBCL (55%), 32 cases of FL (52%) and 18 cases of MALT-L (28%). It is widely distributed in the genome, but more frequently found in 1p, 1q, 6p, 6q and 12q. High-grade amplifications and homozygous deletions frequently provide a clue to identify relevant gene targets. In our series, 12 loci of high-grade amplifications and 14 loci of homozygous deletions were identified, and helped to specify the candidate genes. These regions included, FCGR2B amplified in 5 cases of DLBCL, RERE amplified in 2 cases of FL and CDKN2A/CDKN2B deleted in 9 cases of DLBCL. The most notable finding in the current study was, however, the identification of common genomic alterations in genes that regulate activation of NFkB pathway in more than 50% of B-NHL cases. Eight lymphoma cases harbored high-grade amplification of cREL gene, and gain including cREL was detected in 28 samples (14.7%). Fourteen cases had gains or amplification of TRAF6, and another 16 cases had deletion at 10q including PTEN. These abnormalities were supposed to cause dysregulation of NFkB. Aberrant NFkB activity has long been implicated in the pathogenesis of B-NHL, and our study confirmed that dysregulation of NFkB pathway was main mechanism of lymphomagenesis, providing further rationale that he treatment against malignant lymphoma with inhibitor of NF kappa B pathway.

AID is required for germinal center–derived lymphomagenesis

Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.

Activation Induced Cytidine Deaminase (AID) Is Required for Germinal-Center Derived Lymphomagenesis.

Most B cell non-Hodgkin's lymphomas (B-NHL) derive from germinal center (GC) B cells and their pathogenesis is associated with the accumulation of distinct genetic lesions, including chromosomal translocations and a more recently identified mechanism of genomic instability, termed aberrant somatic hypermutation. These alterations are thought to be due to mistakes occurring during two GC-associated immunoglobulin (Ig) genes remodeling processes: class switch recombination (CSR) and somatic hypermutation (SHM). However, this model has never been formally proven. To conclusively investigate the role of CSR and SHM in the pathogenesis of B-NHL, we examined whether lymphoma development in mice requires the function of activation induced cytidine deaminase (AID), a DNA editing enzyme expressed specifically in GC and activated B cells and essential for both processes. Three transgenic mouse models were generated by crossing lymphoma-prone mice (λMYC, λMYC/IμHABCL6 and IμHABCL6) with mice (AID−/−) that are unable to undergo both SHM and CSR. The λMYC mice develop a diffusely infiltrating monoclonal proliferation of pre-GC origin, with unmutated IgV genes and lack of BCL6 expression, and therefore presumably independent from AID-associated DNA remodeling events. Conversely, lymphomas in λMYC/IμHABCL6 and IμHABCL6 mice recapitulate GC/post GC-derived malignancies, in that the former display somatically mutated IgV genes and upregulation of post-GC markers (CD138) in most of the cases, while the latter develop a splenic lymphoproliferative syndrome that culminates, past 12 months of age, in clonal B cell lymphomas with DLBCL morphology and somatically mutated IgV genes (~70% of the animals) (Cattoretti et al., Cancer Cell 7:445–455, 2005). Mice were monitored for tumor incidence and survival, and a combination of histologic, immunophenotypic and gene expression profiling analysis was used for tumor characterization. As expected, no significant differences in event-free survival and lymphoma type were observed between AID-proficient and AID-deficient λMYC mice, in agreement with their pre-GC derivation. Conversely, a phenotypic shift of the tumor was observed in λMYC/IμHABCL6 mice when bred into an AID−/− background, with >80% of the cases (N=21/26) reverting to a pre-GC phenotype (loss of GC/post GC markers) undistinguishable from that of the λMYC and λMYC/AID−/− mice. Gene expression profile analysis on representative cases (N=10 λMYC/IμHABCL6 and 5 each for λMYC, λMYC/AIDKO, λMYC/IμHABCL6/AIDKO) confirmed significant phenotypic similarities between pre-GC derived λMYC lymphomas and the λMYC/IμHABCL6/AID −/− lymphomas, which co-segregated in a separate cluster from λMYC/IμHABCL6 tumors. Analogously, a significant reduction in DLBCL frequency was observed in the IμHABCL6/AIDKO cohort as compared to IμHABCL6 mice (N= 4/19, 21% vs 8/14, 57%; p=0.03).Taken together, these results indicate that GC-derived lymphomas cannot develop in the absence of AID, thereby providing direct support to the notion that AID-mediated mistakes in antigen receptor gene modification events (CSR and SHM) represent major contributors to B-NHL pathogenesis.

MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma

AbstractThe MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expression may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification. First, 2 cases, one case of MALT lymphoma and another of aggressive marginal zone lymphoma (MZL) with t(14;18)(q32;q21), cytogenetically identical to the translocation involving BCL2, were shown by fluorescence in situ hybridization (FISH) to involve MALT1, which lies about 5 Mb centromeric of BCL2. Molecular cloning of both by long-distance inverse polymerase chain reaction showed breakpoints lying 1 to 2 kilobase (kb) centromeric of the first 5′ MALT1 exon; both cases showed MALT1 overexpression at either RNA or protein levels. Second, we examined the structure and gene expression profile of genomic amplifications involving 18q21 in a panel of 40 B-NHL cell lines using comparative genomic hybridization to microarrays (array CGH) and gene expression profiling techniques. Using array CGH, 2 peaks of genomic amplification were observed, one centered around BCL2 and the other around MALT1.Ofthe 3 cell lines with MALT1 amplification, 2 showed MALT1 overexpression as assessed by gene profiling, quantitative reverse transcription–polymerase chain reaction (QRT-PCR), and Western blotting. To determine if comparable events occurred in primary MALT and splenic MZL tumors, 40 cases were analyzed by FISH or QRT-PCR; genomic amplification and MALT1 overexpression were seen in 2 cases. Together, these data implicate MALT1 as a dominant oncogene that may play a role in the pathogenesis of B-NHL.

Detection of hepatitis C virus RNA sequences in B-cell non-Hodgkin lymphoma.

Serologic testing shows that hepatitis C virus (HCV) may have a role in the pathogenesis of B-cell non-Hodgkin lymphomas (B-cell NHLs). We tried to demonstrate HCV RNA sequences in paraffin-embedded tissue from B-cell NHLs by reverse-transcription double polymerase chain reaction (RT-PCR) and Southern blotting. We studied 31 consecutive cases of B-cell NHLs; lymph nodes from 32 patients with diseases other than B-cell NHL were negative controls. Positive-strand HCV RNA was tested with primers for the 5' untranslated region. Replicative negative strand HCV RNA was tested with strand-specific RT-PCR for the 5' untranslated region. Immunohistochemical staining for HCV was done using an antibody to HCV core protein. Positive-strand HCV RNA was detected in 8 patients with B-cell NHL; negative-strand HCV RNA was detected in 6 of these cases, indicating viral replication. All control cases were negative for HCV RNA. Immunohistochemistry showed no staining of lymphoma cells for HCV core proteins in any case. HCV and B-cell NHLs may be associated. RT-PCR on paraffin-embedded lymphoma tissue is an alternative method of testing for HCV. The value of immunohistochemistry could not be ascertained. The exact role of HCV in the pathogenesis of B-cell NHL needs to be studied further.