Burkitt Lymphoma Research Articles

Inhibition of MST1/2 Kinases of the Hippo Signaling Pathway Enhances Antitumor Chemotherapy in Hematological Cancers.

Primary drug resistance of tumor cells or resistance acquired during treatment is among the main factors that significantly limit the efficacy of antitumor chemotherapy, along with severe side effects depending on the drug dose. To increase the efficacy, chemotherapeutics can be used in combination with substances that modulate the functions of cell signaling pathways. In this work, the substance XMU-MP-1, an inhibitor of key MST1/2 kinases of the Hippo signaling pathway, was shown to enhance the antitumor activity of two genotoxic chemotherapeutics, etoposide and cisplatin, against Namalwa Burkitt's B-cell lymphoma cells. XMU-MP-1 increased the cytotoxicity of the agents and significantly reduced their CTD50. The drug efficacy is therefore possible to increase significantly, and a therapeutic effect might be achieved at a lower drug concentration to reduce the likelihood of life-threatening side effects.

Real-World Data on Lymphoma in Adolescents and Young Adults (AYA)-Report From the Lymphoma and Related Diseases Registry (LaRDR).

Lymphoma is a common malignancy among adolescents and young adults (AYAs) which is generally defined as 15-39 years. Relative to other age groups, lymphoma in AYAs remains understudied with heterogeneous treatment options. We performed a retrospective review of patients aged 18-60 years in the Australasian Lymphoma and Related Diseases Registry (LaRDR) with new diagnoses of the common subtypes of lymphoma in AYAs between January 2016 and April 2023. The subtypes are classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and Burkitt lymphoma (BL). Patient demographics, disease characteristics, treatment and outcome data were collected, and comparisons were made between AYAs (18-39 years) and older adults (OAs) (aged 40-60). AYAs had higher rates of cHL and PMBCL whereas OAs presented more frequently with DLBCL. AYAs with cHL and PMBCL had higher rates of early-stage and low-risk disease than OAs. In contrast, both AYAs and OAs were more likely to present with advanced-stage DLBCL and BL. AYAs with cHL were more likely to be treated with BEACOPP as compared to OAs who were more commonly treated with ABVD. There was no significant difference in treatment regimens for DLBCL, PMBCL or BL between AYAs and OAs. AYAs with cHL had better overall survival (OS) compared to OAs; specifically, cHL AYAs had better OS and DLBCL AYAs had better progression-free survival (PFS) and OS compared to OAs. The study provides valuable data on patient and disease characteristics, treatments used and outcomes in AYA compared to OA aged 40-60 years. Registry data such as from LaRDR can help improve treatment standardisation and AYA patient outcomes. The authors have confirmed clinical trial registration is not needed for this submission.

Cost-effectiveness and budget impact of covering Burkitt lymphoma in children under Ghana’s National Health Insurance Scheme

BackgroundChildhood cancer is not a high priority in health care financing for many countries, including in Ghana. Delayed care seeking and treatment abandonment, often due to the financial burden of care seeking to families, are common reasons for a relatively low overall survival (OS) in low-and middle-income countries. In this study, we analyzed the cost-effectiveness of extending health insurance coverage to children with Burkitt lymphoma (BL) in Ghana.MethodsWe developed a Markov model in Microsoft Excel to estimate the costs and effects of BL treatment when National Health Insurance Scheme (NHIS) was provided compared to the status quo where NHIS does not cover care for childhood cancer. The analysis was undertaken from the societal and health system (payer) perspective. Both costs (measured in $) and effects, measured using disability adjusted life years (DALYs), were discounted at a rate of 3%. The time horizon was a lifetime. Probabilistic sensitivity analysis was done to assess uncertainty in the measurement of the incremental cost-effectiveness ratio (ICER). A budget impact analysis was undertaken from the perspective of the NHIS.ResultsIn the base-case analysis, the intervention (NHIS reimbursed treatment) was less costly than current practice ($8,302 vs $9,558). The intervention was also more effective with less DALYs per patient than the standard of care (17.6 vs 23.33). The ICER was -$219 per DALY averted from societal perspective and $113 per DALY averted from health system perspective. The probabilistic sensitivity analysis showed that the intervention is likely to be both less costly and more effective than current practice in 100% of the 1,000 simulations undertaken.ConclusionProviding health insurance coverage to children with BL is potentially cost-effective. The effectiveness and cost-savings relating to this strategy is driven by its positive impact on treatment initiation and retention. Based on this evidence, there has been a policy change where Ghana’s NHIS has prioritized financing for cancer treatment in children.

Navigating the Therapeutic Landscape of Head and Neck Burkitt’s Lymphoma: A Comparative Analysis of Treatment Approaches and Associated Challenges.

Head and neck Burkitt lymphoma (HN-BL) requires tailored treatment strategies due to its unique anatomical location and aggressive nature. HN-BL poses distinctive diagnostic and therapeutic obstacles in contrast to its extranodal equivalents. This review comparatively analyzes current treatment approaches for HN-BL, including intensive chemotherapy regimens, radiation therapy strategies, and the emerging role of targeted therapies. We investigate the effectiveness and adverse effect profiles of these methodologies, emphasizing determinants that affect treatment choice including neoplasm stage, patient functional capacity, and the existence of comorbid conditions. Furthermore, the abstract discusses challenges in managing treatment-related complications, achieving optimal local control, and addressing the specific anatomical challenges posed by head and neck involvement. Finally, we explore areas requiring further investigation to improve outcomes and refine therapeutic strategies for this aggressive malignancy.

Audit of B-cell Cancer Genes.

Comprehensive genetic analysis of tumors with exome or whole genome sequencing has enabled the identification of the genes that are recurrently mutated in cancer. This has stimulated a series of exciting advances over the past 15 years, guiding us to new molecular biomarkers and therapeutic targets among the common mature B-cell neoplasms. In particular, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Burkitt lymphoma (BL) have each been the subject of considerable attention in this field. Currently, more than 850 genes have been reported as targets of protein-coding mutations in at least one of these entities. To reduce this to a manageable size, we describe a systematic approach to prioritize and categorize these genes, based on the quality and type of supporting data. For each entity, we provide a list of candidate driver genes categorized into Tier 1 (high-confidence genes), Tier 2 (candidate driver genes), or Tier 3 (lowest-confidence genes). Collectively, this reduces the number of high-confidence genes for these three lymphomas to a mere 144. This further affirms the substantial overlap between the genes relevant in DLBCL and each of FL and BL. These highly curated and annotated gene lists will continue to be maintained as a resource to the community. These results emphasize the extent of the knowledge gap regarding the role of each of these genes in lymphomagenesis. We offer our perspective on how to accelerate the experimental confirmation of drivers using a variety of model systems, using these lists as a guide for prioritizing genes.

Refining prognostic assessment of diffuse large B-cell lymphoma: insights from multi-omics and single-cell analysis unveil SRM as a key target for regulating immunotherapy

PurposesPrevious studies have demonstrated that proliferation, stroma or immunity strongly influence the prognosis and therapeutic resistance of diffuse large B-cell lymphoma (DLBCL). Herein, we aimed to integrate proliferation, stromal, and immune (PSI) features to systematically evaluate the risk stratification and explore novel therapeutic targets in DLBCL.MethodsUsing data from multiple researches, we comprehensively evaluated the characteristics and prognostic impact of PSI features in DLBCL, and developed a novel risk stratification model (PSI score) with a consistent cutoff value to stratify the risk of 3,229 DLBCL patients from different cohorts. Mechanisms underlying adverse prognosis in the high-risk DLBCLs were investigated through transcriptomic (n = 3,229), genomic (n = 576), and scRNA-seq (n = 20) analyses.ResultsWe identified a high-risk DLBCL subgroup (HPSI, 36.1% of DLBCL). HPSI was characterized by upregulation of spermidine synthase (SRM) and cold tumor microenvironment (TME). Compared to low-risk group, HPSI exhibited poorer prognosis, with lower 3-year OS (51.7% vs. 78.1%, P < 0.0001) and PFS (48.9% vs. 72.6%, P < 0.0001) rates. HPSI shared malignant proliferative phenotype resembling Burkitt lymphoma. Genomic analysis revealed extensive copy-number loss in the chemokine and interleukin coding regions within HPSI. Bulk and scRNA-seq analyses indicated that upregulation of SRM might mediate cold TME in DLBCL, potentially through suppressing immune activation pathways, promoting dendritic cells (DCs) transformation into tolerogenic DCs, and facilitating M2 polarization of macrophages. Finally, for eventual clinical translation, we integrated the model with other clinical features to develop a comprehensive database for DLBCL.ConclusionOur study effectively simplifies risk stratification of DLBCL, revealing that immune microenvironment and SRM jointly shape a subgroup of DLBCL with extremely poor prognosis. Targeting SRM may become a potential strategy for modulating immunotherapy in DLBCL, providing new insight for immunotherapy.

Combining CRISPR activation and interference capabilities using dCas9 and G-quadruplex structures.

We demonstrate that both Clustered regularly interspaced short palindromic repeats (CRISPR) interference and CRISPR activation can be achieved at RNA and protein levels by targeting the vicinity of a putative G-quadruplex (GQ)-forming sequence (PQS) in the c-Myc promoter with nuclease-dead Cas9 (dCas9). The achieved suppression and activation in Burkitt's Lymphoma cell line and in in vitro studies are at or beyond those reported with alternative approaches. When the template strand (contains the PQS) was targeted with CRISPR-dCas9, the GQ was destabilized and c-Myc mRNA and protein levels increased by 2.1- and 1.6-fold, respectively, compared to controls in the absence of CRISPR-dCas9. Targeting individual sites in the nontemplate strand (NTS) with CRISPR-dCas9 reduced both the c-Myc mRNA and protein levels (by 1.8- and 2.5-fold, respectively), while targeting two sites simultaneously further suppressed both the mRNA (by 3.6-fold) and protein (by 9.8-fold) levels. These were consistent with cell viability assays when single or dual sites in the NTS were targeted (1.7- and 4.7-fold reduction in viability, respectively). We also report extensive in vitro biophysical studies which are in quantitative agreement with these cellular studies and provide important mechanistic details about how the transcription is modulated via the interactions of RNA polymerase, CRISPR-dCas9, and the GQ.

Resveratrol as a BCL6 natural inhibitor suppresses germinal center derived Non-Hodgkin lymphoma cells growth.

Non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and follicular lymphoma (FL), predominantly arise from B cells undergoing germinal center (GC) reactions. The transcriptional repressor B-cell lymphoma 6 (BCL6) is indispensable for GC formation and contributes to lymphomagenesis via its BTB domain-mediated suppression of target genes. Dysregulation of BCL6 underpins the pathogenesis of GC-derived NHL. While pharmacological targeting the BCL6-BTB domain has shown therapeutic promise, natural product-based inhibitors remain underexplored. In this study, resveratrol, a polyphenolic compound derived from grapes, was identified as a potent BCL6 inhibitor through a comprehensive screen of traditional Chinese medicine monomers using Homogeneous Time-Resolved Fluorescence (HTRF) assay. As a BCL6 natural inhibitor, resveratrol effectively disrupted the BCL6/SMRT interaction, reactivated suppressed gene expression, and inhibited the proliferation of GC-derived NHL cells. It also exhibited synergistic efficacy when combined with EZH2 and PRMT5 inhibitors. In vivo, resveratrol suppressed GC formation, reduced follicular helper T-cell frequencies, impaired class-switch recombination, and disrupted immunoglobulin affinity maturation. Furthermore, it markedly inhibited the progression of GC-derived NHL in animal models. Our findings demonstrate that resveratrol functions as a natural BCL6 inhibitor with significant therapeutic potential for the treatment of GC-derived NHL.

Advances in the Classification of Aggressive B-cell Lymphomas.

Aggressive B-cell lymphomas are a biologically and clinically very heterogeneous group of tumors that may be related to different stages of B-cell differentiation development. This review aims to summarize recent advances in the understanding of these tumors with a focus on the practical approach to the diagnosis of these entities. We analyze the defining characteristics of the different subtypes of aggressive B-cell lymphomas, including nodal and extranodal diffuse large B-cell lymphoma, virus-associated lymphomas, terminally differentiated B-cell lymphomas, high-grade B-cell lymphomas, and Burkitt lymphoma. This review particularly explores the integration of morphologic, immunophenotypic, and genetic data that refine diagnostic accuracy and prognostic stratification, underscoring the necessity for a standardized approach in clinical practice. By synthesizing current knowledge, this review aims to enhance the understanding of aggressive B-cell lymphomas within the context of the evolving classification system, paving the way for future research and clinical advancements.

Patterns of incident Burkitt lymphoma during the HIV epidemic among the Black African and White population in South Africa.

Burkitt lymphoma (BL) may be HIV-associated but data on BL trends in South Africa (SA), where HIV is highly prevalent, are scarce. We compared BL incidence trends over 36 years among Black African and White individuals. We included histologically diagnosed BL from the National Cancer Registry in SA between 1986-2021. We computed yearly age-standardised incidence rates (ASIR) by race, and annual percentage changes in ASIR using Joinpoint regression. Between 1986-2021, 2205 Black African (ASIR: 1.68/1,000,000; 95% confidence interval [CI] 1.63-1.73) and 366 White individuals (ASIR: 2.34/1,000,000; 95% CI 2.15-2.53) had incident BL. Median age at diagnosis increased over time, while the male proportion among those diagnosed declined. The ASIR among Black Africans increased from 1986-2012 and declined thereafter with BL incidence peaks shifting from children and elderly to middle-aged adults. Among White individuals, BL rates rose among all agegroups over time. The BL epidemiology among Black Africans, with decreasing rates since 2012, may reflect SA's evolving HIV epidemic. In contrast, BL rates among White individuals in SA and many high-income countries continue to increase over time. Further studies are needed to better understand the differences in BL epidemiology across geographic regions and population groups.

The Histone Demethylase LSD1/ZNF217/CoREST Complex is a Major Restriction Factor of Epstein-Barr Virus Lytic Reactivation.

Epstein-Barr virus (EBV) contributes to ~1.5% of human cancers, including lymphomas, gastric and nasopharyngeal carcinomas. In most of these, nearly 80 viral lytic genes are silenced by incompletely understood epigenetic mechanisms, precluding use of antiviral agents such as ganciclovir to treat the 200,000 EBV-associated cancers/year. To identify host factors critical for EBV latency, we performed a human genome-wide CRISPR-Cas9 screen in Burkitt B-cells. Top hits included the lysine-specific histone demethylase LSD1 and its co-repressors ZNF217 and CoREST. LSD1 removes histone 3 lysine 4 (H3K4) and histone 3 lysine 9 (H3K9) methylation marks to downmodulate chromatin activation. LSD1, ZNF217 or CoREST knockout triggered EBV reactivation, as did a LSD1 small molecule antagonist, whose effects were additive with histone deacetylase inhibition. LSD1 blockade reactivated EBV in Burkitt lymphoma, gastric carcinoma and nasopharyngeal carcinoma models, sensitized cells to ganciclovir cytotoxicity and induced EBV reactivation in murine xenografts. ZNF217 and LSD1 co-occupied the EBV immediate early gene BZLF1 promoter, which drives B-cell lytic cycle, as well as to the oriLyt enhancer regions recently implicated in EBV reactivation. LSD1 depletion increased levels of activating histone 3 lysine 4 (H3K4) methylation but not repressive histone lysine 9 methylation marks at BZLF1 and oriLyt and induced their interaction by long-range DNA looping. An orthogonal CRISPR screen highlighted a key H3K4 methyltransferase KMT2D role in driving EBV reactivation. Our results highlight H3K4 methylation as a major EBV lytic switch regulator and suggest novel therapeutic approaches.

Burkitt lymphoma: an unusual location in children, report of a case

Burkitt lymphoma: an unusual location in children, report of a case

Implications of EBV-Encoded and EBV-Related miRNAs in Tumors.

Over 90% of people are infected with the human g-herpesvirus known as the Epstein- Barr virus (EBV). Cancers, such as gastric carcinoma, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and Burkitt lymphoma, are thought to be linked with EBV. It is noteworthy that the first virus discovered that encodes microRNAs (miRNAs) was EBV, and these miRNAs show expression at the different phases of EBV infection. There is growing evidence that EBV-encoded miRNAs influence the growth of EBV-associated tumors. These EBV miRNAs, i.e., BamHI-H rightward fragment 1-derived microRNAs (BHRF1miRNA) and BamHI-A rightward fragment-derived microRNAs (BART miRNAs), are crucial for the persistence of viral infection and the avoidance of host defenses. Currently, significant advancements have been made in analyzing the microRNAs that are found in the duration of EBV infection, in vitro studies identified molecular targets of miRNAs and in vivo studies enhanced our understanding regarding the pathophysiology of these molecules. An extensive look into the pro-carcinogenic impact of microRNAs associated with EBV will increase our understanding of the molecular mechanisms of EBV-associated tumors. In this paper, we have highlighted the functions of miRNAs in EBV infection as well as recent developments in miRNA-based therapeutic and diagnostic approaches that could be useful for EBV-related malignancies. Significantly, targeted therapies against EBV miRNAs are advancing rapidly, with emerging approaches such as miRNA sponges, anti-miRNA oligonucleotides, and CRISPR/Cas9 technologies. These innovations indicate the imminent onset of a new era in the treatment of EBV-associated tumors.

1990-2041 Global burden of Burkitt lymphoma with 20 years forecast: A systematic analysis using the global burden disease of study of 2021.

To investigate the trends in Burkitt lymphoma incidence, mortality, and disability-adjusted life-years, considering sex and age, from 1990 to 2021, with a 20-year forecast. Data regarding Burkitt lymphoma were extracted from the Global Burden of Disease study for the year 2021. Globally, there were 19,072 incident cases of Burkitt lymphoma in 2021. Cases of Burkitt lymphoma experienced a 207% increase from 1990 to 2021. Over three decades, Burkitt lymphoma-associated deaths rose from 3843 to 6525. The global incidence rate of Burkitt lymphoma increased from 0.127 in 1990 to 0.236 in 2021 per 100,000 population. High body-mass indexes contribution to Burkitt lymphoma is evident in the disability-adjusted life-years, with the United States and the United Kingdom recording 0.06 and 0.05, respectively. Conversely, China and India demonstrated substantially lower contributions, at 0.02 and 0.005, respectively. The groups aged 0-14 and 50-74 years surpassed other age groups in both Burkitt lymphoma-associated incidence and death numbers. Moreover, males consistently had higher Burkitt lymphoma-associated mortality rates and numbers than females in all age groups. Furthermore, the estimated annual percentage changes of incidence with Burkitt lymphoma were positively correlated with sociodemographic index (Pearson r = 0.606; p = 0.003). The Bayesian age-period-cohort model predicts a significant increase in the age-standardized incidence rates of Burkitt lymphoma over the next 20 years. Interestingly, the age-standardized rates of death did not change dramatically from 1990 to 2021; and the trend is expected to remain relatively stable in the future 20 years. The burden of Burkitt lymphoma varies according to different regions and genders, and children of 0-14 years, adults of 50-74 years with Burkitt lymphoma disease as well as male patients need special attention. High body-mass index contributes significantly to Burkitt lymphoma burden in the United States and United Kingdom, but less so in China and India. Hopefully, this study will help optimize the prevention, diagnosis, treatment, and management of Burkitt lymphoma to reduce the disease burden.

MicroRNA Expression in High-Grade B-Cell Lymphoma With 11q Aberration.

Mature aggressive B-cell lymphomas, such as Burkitt lymphoma (BL) and Diffuse large B-cell lymphoma (DLBCL), show variations in microRNA (miRNA) expression. The entity of High-grade B-cell lymphoma with 11q aberration (HGBCL-11q) shares several biological features with both BL and DLBCL but data on its miRNA expression profile are yet scarce. Hence, this study aims to analyze the potential differences in miRNA expression of HGBCL-11q compared to BL and DLBCL. We evaluated the expression profiles of 2083 miRNAs in 25 HGCBL-11q, 7 BL, 131 DLBCL, and tonsils using the HTG EdgeSeq miRNA whole transcriptome assay. Uniform manifold approximation and projection (UMAP) and differential gene expression analyses based on DESeq2 were carried out. UMAP analysis of miRNA expression did not reveal distinct groups among the studied lymphomas. However, differential gene expression investigations detected sets of overexpressed miRNAs in HGBCL-11q when compared to BL (miR-9-3p, miR-9-5p, miR-3919, miR-129-1-3p, miR-129-2-3p, miR-331-3p, miR-196b-5p, and miR-28-5p) and DLBCL (miR-3919, miR-1290, miR-4538, and miR-4791), respectively. Notably, miR-3919 showed heterogeneous but significantly higher expression (p-value < 0.001) in HGBCL-11q than in both, BL and DLBCL. We identified a group of differentially expressed miRNAs between HGBCL-11q vs. BL and DLBCL, with miR-3919 as the most commonly and recurrently overexpressed miRNA in HGBCL-11q.

Assessment of Treatment Outcomes and Associated Factors Among Pediatric Patients With Burkitt Lymphoma at Kenyatta National Hospital.

In developing countries, the treatment outcomes of Burkitt lymphoma are poor due to the poorly equipped healthcare systems. In addition, there is limited comprehensive data within the African continent, including Kenya, about the outcomes of treatment for this cancer. To assess treatment outcomes and variables associated with an increased risk of death from disease progression or treatment-related toxicities among Burkitt lymphoma pediatric patients at the Kenyatta National Hospital (KNH). A retrospective one-arm cohort study was conducted to examine the treatment outcomes of pediatric patients with Burkitt lymphoma. All eligible Burkitt lymphoma pediatric patients treated between January 1, 2016 and December 31, 2022 were included. The patients were retrospectively monitored from the initial cancer diagnosis until either death or the last follow-up appointment visit in the facility. Data analysis of factors associated with treatment and disease progression-related death was carried out using the SPSS version 29.0 software. Kaplan-Meier survival and Cox regression analyses were employed to determine the survival time and predictors of mortality, respectively. The median age of the patients at diagnosis was 6 years (range: 3-13 years). The majority of patients were diagnosed with Stage IV disease accounting for 46.7% of all patients. Of the 75 patients studied, 24% (18) of them were died. The 5-year overall survival rate was 70%, and most patients had stable disease during the follow-up period. Patients with Stage IV disease who were treated with full-fuse chemotherapy were 19.2 (AHR = 19.2, 95% CI = 5.2-48.5, p < 0.001) and 7.4 times (AHR = 7.4, 95% CI = 2.2-19.9, p = 0.003) more hazard of dying as compared to patients without metastasis and received a combination of radiation and reduced-dose chemotherapy, respectively. However, the age, gender, stage of cancer, histological type of cancer, and co-morbidity were not significant predictors of survival. Because of the retrospective nature of the study design, the data accuracy relied on the proper documentation of medical records in the study setting. The 5-year overall survival rate among pediatric burkitt's lymphoma patients was above average as compared to other African countries. Most patients had reduced tumor size and stable disease during the follow-up period. Metastases and full-fuse chemotherapy were significant predictors of mortality.

Targeted Next-Generation Sequencing of Cell-Free DNA to Detect MYC-Immunoglobulin Translocation and Epstein-Barr Virus DNA in Plasma of Burkitt Lymphoma Patients in East Africa.

Epstein-Barr virus (EBV)-positive Burkitt lymphoma (BL) affects children in sub-Saharan Africa, but diagnosis via tissue biopsy is challenging. We explored a liquid biopsy approach using targeted next-generation sequencing to detect the MYC-immunoglobulin (MYC-Ig) translocation and EBV DNA, assessing its potential for minimally invasive BL diagnosis. The panel included targets for the characteristic MYC-Ig translocation, mutations in intron 1 of MYC, mutations in exon 2 of MYC, and three EBV genes: EBV-encoded RNA (EBER)1, EBER2, and EBV nuclear antigen 2. It was first tested in a small derivation cohort of four precharacterized BL-derived cell lines with known translocation status and eight precharacterized plasma samples with known EBV DNA status by quantitative polymerase chain reaction (qPCR). These different data modalities were combined to assess the accuracy of this approach in the diagnosis of BL in 20 patient plasma samples in Tanzania and Uganda. The next-generation sequencing panel detected three of four MYC-Ig translocations in the BL-derived cell lines. EBV viral load by targeted sequencing correlated strongly with qPCR results (Spearman's rho = 0.94) in precharacterized plasma samples. Using the patient plasma samples, mutations in MYC intron 1 were associated with the presence of a MYC translocation with 25 or more mutations being predictive of a translocation with AUC, sensitivity, and specificity of 1. Overall, liquid biopsy parameters associated with a diagnosis of BL (P < .05) included cell-free DNA concentration, circulating tumor DNA concentration, MYC intron 1 mutations, MYC-Ig translocation, and autosome entropy. Integrating these parameters into a diagnostic model demonstrated excellent performance with an AUC of 0.95, sensitivity of 0.9, and specificity of 1. This analysis demonstrates the potential of liquid biopsy to improve BL diagnosis in settings with limited pathology resources. Validation of our approach in a larger data set is needed.

Burkitt's lymphoma: clinical image of a rare but nasty cancer

Burkitt's lymphoma: clinical image of a rare but nasty cancer

USP7 Inhibitors Destabilize EBNA1 and Suppress Epstein-Barr Virus Tumorigenesis.

Epstein-Barr virus (EBV) is a ubiquitous human ɣ-herpesvirus implicated in various malignancies, including Burkitt's lymphoma and gastric carcinomas. In most EBV-associated cancers, the viral genome is maintained as an extrachromosomal episome by the EBV nuclear antigen-1 (EBNA1). EBNA1 is considered to be a highly stable protein that interacts with the ubiquitin-specific protease 7 (USP7). Here, we show that pharmacological inhibitors and small interfering RNA (siRNA) targeting USP7 reduce EBNA1 protein levels in a proteosome-dependent manner. Proteomic analysis revealed that USP7 inhibitor GNE6776 altered the EBNA1 protein interactome, including disrupting USP7 association with EBNA1. GNE6776 also inhibited EBNA1 binding to EBV oriP DNA and reduced viral episome copy number. Transcriptomic studies revealed that USP7 inhibition affected chromosome segregation and mitotic cell division pathways in EBV+ cells. Finally, we show that GNE6776 selectively inhibited EBV+ gastric and lymphoid cell proliferation in cell culture and slowed EBV+ tumor growth in mouse xenograft models. These findings suggest that USP7 inhibitors perturb EBNA1 stability and function and may be exploited to treat EBV latent infection and tumorigenesis.

MicroRNA Profile of High-Grade B-Cell Lymphoma with 11q Aberration.

High-grade B-cell lymphoma with 11q aberration (HGBCL-11q) is a rare germi-nal centre lymphoma characterised by a typical gain/loss pattern on chromo-some 11q but without MYC translocation. It shares some features with Burkitt lymphoma (BL), HGBCLs and germinal centre-derived diffuse large B-cell lym-phoma, not otherwise specified (GCB-DLBCL-NOS). Since microRNA expression in HGBCL-11q remains unknown, we aimed to identify and compare the mi-croRNA expression profiles in HGBCL-11q, BL and in GCB-DLBCL-NOS. Next-generation sequencing (NGS)-based microRNA profiling of HGBCL-11q (n = 6), BL (n = 8), and GCB-DLBCL-NOS without (n = 3) and with MYC rearrange-ment (MYC-R) (n = 7) was performed. We identified sets of 39, 64, and 49 mi-croRNAs differentiating HGBCL-11q from BL, and from GCB-DLBCL-NOS without MYC-R, respectively. The expression levels of miR-223-3p, miR-193b-3p, miR-29b-3p, and miR-146a-5p consistently differentiated HGBCL-11q from both BL, GCB-DLBCL-NOS without MYC-R. In addition, HGBCL-11q presented greater heterogeneity in microRNA expression than BL. The expression profile of MYC-regulated microRNAs differed in HGBCL-11q and in BL, while also clearly distinguishing HGBCL-11q and BL from GCB-DLBCL-NOS. The microRNA pro-file of HGBCL-11q differs from those of BL and GCB-DLBCL-NOS, exhibiting greater heterogeneity compared to BL. The microRNA profile further supports that HGBCL-11q is a distinct subtype of B-cell lymphoma.