Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis.

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.

Aflatoxin B1 and Epstein-Barr virus-induced CCL22 expression stimulates B cell infection.

Epstein-Barr Virus (EBV) infects more than 90% of the adult population worldwide. EBV infection is associated with Burkitt lymphoma (BL) though alone is not sufficient to induce carcinogenesis implying the involvement of co-factors. BL is endemic in African regions faced with mycotoxins exposure. Exposure to mycotoxins and oncogenic viruses has been shown to increase cancer risks partly through the deregulation of the immune response. A recent transcriptome profiling of B cells exposed to aflatoxin B1 (AFB1) revealed an upregulation of the Chemokine ligand 22 (CCL22) expression although the underlying mechanisms were not investigated. Here, we tested whether mycotoxins and EBV exposure may together contribute to endemic BL (eBL) carcinogenesis via immunomodulatory mechanisms involving CCL22. Our results revealed that B cells exposure to AFB1 and EBV synergistically stimulated CCL22 secretion via the activation of Nuclear Factor-kappa B pathway. By expressing EBV latent genes in B cells, we revealed that elevated levels of CCL22 result not only from the expression of the latent membrane protein LMP1 as previously reported but also from the expression of other viral latent genes. Importantly, CCL22 overexpression resulting from AFB1-exposure in vitro increased EBV infection through the activation of phosphoinositide-3-kinase pathway. Moreover, inhibiting CCL22 in vitro and in humanized mice in vivo limited EBV infection and decreased viral genes expression, supporting the notion that CCL22 overexpression plays an important role in B cell infection. These findings unravel new mechanisms that may underpin eBL development and identify novel pathways that can be targeted in drug development.

Burkitt lymphoma risk shows geographic and temporal associations with Plasmodium falciparum infections in Uganda, Tanzania, and Kenya.

Endemic Burkitt lymphoma (eBL) is a pediatric cancer coendemic with malaria in sub-Saharan Africa, suggesting an etiological link between them. However, previous cross-sectional studies of limited geographic areas have not found a convincing association. We used spatially detailed data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) study to assess this relationship. EMBLEM is a case-control study of eBL from 2010 through 2016 in six regions of Kenya, Uganda, and Tanzania. To measure the intensity of exposure to the malaria parasite, Plasmodium falciparum, among children in these regions, we used high-resolution spatial data from the Malaria Atlas Project to estimate the annual number of P. falciparum infections from 2000 through 2016 for each of 49 districts within the study region. Cumulative P. falciparum exposure, calculated as the sum of annual infections by birth cohort, varied widely, with a median of 47 estimated infections per child by age 10, ranging from 4 to 315 infections. eBL incidence increased 39% for each 100 additional lifetime P. falciparum infections (95% CI: 6.10 to 81.04%) with the risk peaking among children aged 5 to 11 and declining thereafter. Alternative models using estimated annual P. falciparum infections 0 to 10 y before eBL onset were inconclusive, suggesting that eBL risk is a function of cumulative rather than recent cross-sectional exposure. Our findings provide population-level evidence that eBL is a phenotype related to heavy lifetime exposure to P. falciparum malaria and support emphasizing the link between malaria and eBL.

Effect of Malaria Infection on Epstein-Barr Virus Persistence in Kenyan Children.

BACKGROUND: The 2 cofactors in the etiology of Burkitt lymphoma (BL) are Epstein-Barr virus (EBV) and repeated Plasmodium falciparum malaria infections. This study evaluated EBV loads in mucosal and systemic compartments of children with malaria and controls. Age was analyzed as a covariate because immunity to malaria in endemic regions is age dependent. METHODS: Children (2-10 years) with clinical malaria from Western Kenya and community controls without malaria were enrolled. Saliva and blood samples were collected, EBV viral load was assessed by quantitative polymerase chain reaction, and EpiTYPER MassARRAY was used to assess methylation of 3 different EBV genes. RESULTS: Regardless of the compartment, we detected EBV more frequently in malaria cases compared to controls, although the difference was not significant. When EBV was detected, there were no differences in viral load between cases and controls. However, EBV methylation was significantly lower in the malaria group compared to controls in both plasma and saliva (P < .05), indicating increased EBV lytic replication. In younger children before development of immunity to malaria, there was a significant effect of malaria on EBV load in peripheral blood mononuclear cells (P = .04). CONCLUSIONS: These data suggest that malaria can directly modulate EBV persistence in children, increasing their risk for BL.

The Treatment of Burkitt Lymphoma With the Berlin-Frankfurt-Münster Protocol With Rituximab and Consolidative Autologous Transplantation.

INTRODUCTION: Intensive treatment approaches are required for adult patients with Burkitt lymphoma (BL), although an univocal standard of care still does not exist. The use of frontline autologous stem cells transplantation (ASCT) is debated. PATIENTS AND METHODS: Between 2004 and 2020, 50 patients with BL were treated with the Berlin-Frankfurt-Münster (BFM). Treatment plan consisted of 3 blocks, A (ifosfamide, vincristine, methotrexate, etoposide, and cytarabine), B (vincristine, cyclophosphamide, methotrexate, and doxorubicin), and C (vindesine, methotrexate, etoposide, and cytarabine), each repeated twice, every 28 days. Rituximab was given at day 1 each block. Intrathecal prophylaxis was given once per each block. ASCT was scheduled at the end of the 6 blocks after conditioning. RESULTS: Median age at onset was 38 years (range 16-72); stages III-IV disease was observed in 82% of cases; bulky disease occurred in 44% of the patients, with B-symptoms in 38%. Stem cell harvest was performed in 72% of patients, who all received a subsequent ASCT. The full 6 blocks treatment was completed in 70% of the patients. The overall response rate was 74%, with a complete response rate of 60%. Ten-year overall survival and progression-free survival were 83.7% and 76.0%, respectively, without reaching the median. Ten-year disease-free survival was 80.3%. Grades 3-4 neutropenia, thrombocytopenia, anemia, and mucositis were seen in 96%, 60%, 32%, and 24% of patients. Infections occurred in 60% of patients. CONCLUSION: Intensive treatment according to BFM protocol, with rituximab and ASCT, appears feasible, safe, and highly effective in adult patients with BL, as confirmed by long-term survival rates reflecting response maintenance.

Insights into the molecular mechanisms of H. pylori-associated B-cell lymphoma.

Cancer research has extensively explored various factors contributing to cancer development, including chemicals, drugs, smoking, and obesity. However, the role of bacterial infections in cancer induction remains underexplored. In particular, the mechanisms underlying H. pylori-induced B-cell lymphoma, a potential consequence of bacterial infection, have received little attention. In recent years, there has been speculation about contagious agents causing persistent inflammation and encouraging B-lymphocyte transition along with lymphomagenesis. MALT lymphoma associated with chronic H. pylori infection, apart from two other central associated lymphomas - Burkitt's Lymphoma and DLBCL, is well studied. Owing to the increasing colonization of H. pylori in the host gut and its possible action in the development of B-cell lymphoma, this review aims to summarize the existing reports on different B-cell lymphomas' probable association with H. pylori infections; also emphasizing the function of the organism in lymphomagenesis; including its interaction with the host, pathogen and host-specific factors, and tumor microenvironment.

Plasma metabolites in childhood Burkitt lymphoma cases and cancer-free controls in Uganda.

INTRODUCTION: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma associated with Plasmodium falciparum and Epstein-Barr virus, both of which affect metabolic pathways. The metabolomic patterns of BL is unknown. MATERIALS AND METHODS: We measured 627 metabolites in pre-chemotherapy treatment plasma samples from 25 male children (6-11 years) with BL and 25 cancer-free area- and age-frequency-matched male controls from the Epidemiology of Burkitt Lymphoma in East African Children and Minors study in Uganda using liquid chromatography-tandem mass spectrometry. Unconditional, age-adjusted logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the BL association with 1-standard deviation increase in the log-metabolite concentration, adjusting for multiple comparisons using false discovery rate (FDR) thresholds and Bonferroni correction. RESULTS: Compared to controls, levels for 42 metabolite concentrations differed in BL cases (FDR < 0.001), including triacylglyceride (18:0_38:6), alpha-aminobutyric acid (AABA), ceramide (d18:1/20:0), phosphatidylcholine ae C40:6 and phosphatidylcholine C38:6 as the top signals associated with BL (ORs = 6.9 to 14.7, P < 2.4✕10- 4). Two metabolites (triacylglyceride (18:0_38:6) and AABA) selected using stepwise logistic regression discriminated BL cases from controls with an area under the curve of 0.97 (95% CI: 0.94, 1.00). CONCLUSION: Our findings warrant further examination of plasma metabolites as potential biomarkers for BL risk/diagnosis.

Optimal dosage of rituximab for children with Burkitt lymphoma.

The current chemotherapy treatments have led to an improvement in survival rates for pediatric Burkitt's lymphoma (BL). Survival in children with high-grade, mature B-cell non-Hodgkin's lymphoma (B-NHL) has been prolonged by six rituximab doses combined with chemotherapy, whereas the efficacy of four doses has not been reported. This study aimed to explore optimal therapeutic strategies-the number of doses of rituximab based on different risk groups-and also aim to investigate the clinical characteristics of Chinese pediatric BL. This study consecutively enrolled children with BL in Beijing Children's Hospital who received French-American-British mature B-cell lymphoma 96 (FAB/LMB96). The patients were divided into three groups: R0 group (chemotherapy alone), R6 group (chemotherapy combined with six rituximab doses), and R4 group (chemotherapy combined with four rituximab doses). The clinical characteristics and outcomes were evaluated. Univariate and multivariate analyses and prognostic nomogram were used to assess prognostic factors. A nomogram was developed that predicted overall survival based on the Cox proportional hazards model, and the concordance index (C-index) and a calibration curve were used to determine its predictive and discriminatory capacity. We enrolled 385 boys and 71 girls, with a median age of 6 years (1-14 years). Of these, 296 patients (65%) had initial abdominal symptoms, 182 (40%) had bulky disease, 46 (10%) had B symptoms, 77 (16.9%) had BL-ALL (blasts ≥ 25% in bone marrow (BM)), 96 (21%) had central nervous system (CNS) disease, 406 (89%) were in stages III-IV, 378 (83%) were in group C, 170 (37.2%) had lactate dehydrogenase (LDH) levels ≥ 1000 U/L at initial diagnosis, and 137 (30%) had tumor lysis syndrome. The R0, R6, and R4 groups included 79, 144, and 227 patients, respectively. Six patients were excluded due to treatment withdrawal for various reasons. The 3-year overall survival (OS) and event-free survival (EFS) percentages were 92% ± 1.3% and 91.3% ± 1.3%, respectively, in all cohorts, whereas the 3-year EFS percentage was 83.5% ± 4.2%, 93% ± 2.1%, and 92.9% ± 1.8% in the R0, R6, and R4 groups, respectively (P = 0.025). The nomogram included four important variables based on a multivariate analysis of the primary cohort: course of disease ≤ 20 days, presence of bulky disease at the beginning of diagnosis, central nervous system(CNS) invasion, and dosage of rituximab. The calibration curve showed that the nomogram was able to predict 3-year OS accurately. The C-index of the nomogram for OS prediction was 0.79 for both cohorts. In our hospital, pediatric BL was more commonly observed in school-age boys with an abdominal mass and mostly in advanced stages at initial diagnosis. The FAB/LMB96 regimen combined with rituximab significantly increased survival outcomes. We observed no significant differences between four and six doses of rituximab in terms of treatment outcomes. The proposed nomogram provides an individualized risk estimate of OS in patients with BL and may assist treatment decision-making or rituximab dose design.

2-[18]F FDG PET/CT dissemination features in adult burkitt lymphoma Are predictive of outcome.

This retrospective study investigated the prognostic role of disease dissemination features (Dmax and Dmaxbsa) measured by 2-[18F]FDG PET/CT in newly diagnosed Burkitt Lymphoma (BL) patients, comparing their performance with other metabolic parameters. We included 78 patients diagnosed with BL between 2010 and 2022 with an available baseline PET, interim PET/CT (iPET) and end of treatment PET/CT (eotPET) and with a minimum of two 2-[18F]FDG avid lesions present at the baseline scan. Dmax was calculated from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) by using LIFEx software; Dmaxbsa was calculated as Dmax normalized for body surface area according to the Du Bois method. We evaluated their effect on metabolic treatment response evaluated by PET, on progression free survival (PFS) and on overall survival (OS). Dmaxbsa was significantly associated with tumor stage, bulky and extranodal disease, MTV and TLG. At a median follow-up of 49 months, the median PFS and OS were 45 and 48 months. Dmax and Dmaxbsa were significantly higher in not complete metabolic response than complete metabolic response group at iPET and eotPET.As far as PFS, parameters including iPET/CT, eotPET/CT outcomes, MTV and TLG showed to be independent prognostic factors while Dmax and Dmaxbsa were not significantly associated with the outcome. Dissemination features, together with eotPET/CT results, MTV and TLG, demonstrated to be significantly correlated with OS. In conclusion, in this study we demonstrated that dissemination features derived by 2[18F]-FDG PET/CT were significantly correlated with response to treatment and long-term outcome, independently from other PET features.

Rituximab with standard LMB chemotherapy in pediatric high-risk mature B-cell non-Hodgkin lymphoma: A report from the JPLSG B-NHL14 trial.

BACKGROUND: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. METHODS: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial. RESULTS: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%. CONCLUSION: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan.

Retrospective analysis of pediatric patients with Burkitt lymphoma treated in Tanzania following the implementation of the 2016 National Treatment Guidelines: Poor outcomes to current standard-of-care therapy.

BACKGROUND: Despite the excellent outcomes achieved in the treatment of pediatric Burkitt lymphoma (BL) in high-income countries (HICs), outcomes remain poor in low- and middle-income countries (LMICs). Efforts to improve BL outcomes in Tanzania included the creation of National Treatment Guidelines in 2016. However, disease outcomes in Tanzania following the creation of these guidelines have not been reported to date. PROCEDURE: Historical records from 2016 to 2021 for patients 0-18 years of age with a diagnosis of BL and seen at Bugando Medical Centre (BMC), in Mwanza, Tanzania, were curated into an electronic database and analyzed descriptively. Patients in this cohort were treated per the Tanzanian National Treatment Guidelines, which include six cycles of cyclophosphamide, vincristine, and methotrexate (COM) chemotherapy with intrathecal methotrexate and cytarabine. RESULTS: In total, 92 BL patients' records were eligible for analysis. Patients in this cohort were most commonly Murphy stage II (28%) or stage III (34%). Nearly all, 91%, met International Network for Cancer Treatment and Research (INCTR) high-risk criteria at presentation. Forty-two percent of patients did not receive a biopsy and were treated with a presumed diagnosis of BL alone. A 1-year event-free survival of 29.6% (95% confidence interval [CI]: 20.3%-39.5%) and a 1-year overall survival of 38.5% (95% CI: 28%-48.9%) were observed. A high rate of treatment abandonment (34%) was also observed. CONCLUSION: In a historical cohort of pediatric patients with BL treated per the 2016 Tanzanian National Treatment Guidelines, we observed poor outcomes and a high rate of abandonment. These outcomes appear inferior to those achieved in the INCTR clinical trial that informed the guidelines' creation, and highlights the importance of "real-world" outcomes data in LMICs. These data reinforce the idea that continued clinical research and capacity building efforts are necessary to improve BL outcomes in LMICs.

Spontaneous tumor lysis syndrome (STLS) during biopsy for burkitt lymphoma: a case report.

BACKGROUND: Tumor lysis syndrome (TLS) is a hematologic oncological emergency characterized by metabolic and electrolyte imbalances. On breakdown of tumor cells, enormous amounts of potassium, phosphate, and nucleic acids are released into systemic circulation. TLS mainly occurs during chemotherapy. However, there are rare incidences of spontaneous tumor lysis syndrome (STLS) prior to commencement of therapy. CASE PRESENTATION: In the case being reported, the child had just undergone a biopsy. As the incision was being closed, there was a sudden onset of high fever, arrhythmia, severe hyperkalemia, hypocalcemia, and acidosis. Following timely symptomatic treatment and continuous renal replacement therapy(CRRT), the child's laboratory results improved, and organ function was restored to normal. The final pathological diagnosis confirmed Burkitt lymphoma. The boy is currently on maintenance chemotherapy. CONCLUSIONS: TLS is a potentially life-threatening complication in hematologic oncology. Several important conclusions can be drawn from this case, reminding clinicians to: (1) be fully aware of the risk factors of TLS and evaluate the level of risk; (2) pay attention to the possibility of STLS during operation, if surgical procedures are necessary and operate with minimal trauma and in the shortest time possibly; (3) take preoperative prophylaxis actively for high-risk TLS patients, including aggressive fluid management and rational use of diuretics and uric-acid-lowering drugs. In addition, this case confirms the effectiveness of CRRT for severe STLS.

The urgency of Burkitt lymphoma diagnosis in fluid cytology-A tertiary care experience.

BACKGROUND: Burkitt lymphoma (BL) is an aggressive high-grade B-cell non-Hodgkin lymphoma commonly diagnosed in young age and is known to involve extra nodal sites. But the involvement of body fluids by BL is an uncommon presentation. Rapid diagnosis of BL is vital to prevent complications like tumour lysis syndrome. Cytological examination of body fluids continues to be an indispensable tool for rapid diagnosis of BL. OBJECTIVES: In this study, we aim to study the clinical, cytomorphological and immunophenotypic characteristics of BL involving serous effusions and other fluids. MATERIALS AND METHODS: In this retrospective study, 17 cases reported as BL in fluid cytology from 2016 to 2022 were collected and reviewed. We performed a comprehensive analysis of the clinical data, cytomorphological features, immunophenotyping data along with the haematological workup of these cases. We have also compared with the histopathological diagnosis for those cases where biopsy was available. RESULTS: BL more commonly involved ascitic fluid (52%), followed by pleural fluid (4 cases) and cerebrospinal fluid (CSF; 4 cases). Primary diagnosis of BL in fluid was done in 88% of the cases. Bone marrow involvement was noted in two cases. Cytological smears showed discrete monomorphous population of medium-sized atypical lymphoid cells with frequent apoptotic bodies. Classic cytoplasmic punched out vacuoles were observed in 88% of the cases. Immunophenotyping data was available for 12 cases in which tumour cells showed positivity for CD20 (100%), CD10 (4 of 7 cases), BCL6 (3 of 5 cases) and cMYC (7 of 7 cases-100%) and were negative for Terminal deoxynucleotidyl transferase (TdT) (11 of 11 cases). Mean Ki67 labelling index was 95%. Histopathological diagnosis was available for 9 cases, and there was 100% agreement between cytological and histopathological diagnosis in 7 cases. CONCLUSION: Precise diagnosis of BL can be rendered in body fluids by identification of classic cytomorphological features and by performing supportive ancillary tests in fluids for immunophenotyping.

Long non-coding RNA as a novel biomarker and therapeutic target in aggressive B-cell non-Hodgkin lymphoma: A systematic review.

Cancer initiation and progression have been associated with dysregulated long non-coding RNA (lncRNA) expression. However, the lncRNA expression profile in aggressive B-cell non-Hodgkin lymphoma (NHL) has not been comprehensively characterized. This systematic review aims to evaluate the role of lncRNAs as a biomarker to investigate their future potential in the diagnosis, real-time measurement of response to therapy and prognosis in aggressive B-cell NHL. We searched PubMed, Web of Science, Embase and Scopus databases using the keywords "long non-coding RNA", "Diffuse large B-cell lymphoma", "Burkitt's lymphoma" and "Mantle cell lymphoma". We included studies on human subjects that measured the level of lncRNAs in samples from patients with aggressive B-cell NHL. We screened 608 papers, and 51 papers were included. The most studied aggressive B-cell NHL was diffuse large B-cell lymphoma (DLBCL). At least 79 lncRNAs were involved in the pathogenesis of aggressive B-cell NHL. Targeting lncRNAs could affect cell proliferation, viability, apoptosis, migration and invasion in aggressive B-cell NHL cell lines. Dysregulation of lncRNAs had prognostic (e.g. overall survival) and diagnostic values in patients with DLBCL, Burkitt's lymphoma (BL), or mantle cell lymphoma (MCL). Furthermore, dysregulation of lncRNAs was associated with response to treatments, such as CHOP-like chemotherapy regimens, in these patients. LncRNAs could be promising biomarkers for the diagnosis, prognosis and response to therapy in patients with aggressive B-cell NHL. Additionally, lncRNAs could be potential therapeutic targets for patients with aggressive B-cell NHL like DLBCL, MCL or BL.

Incidence of Burkitt lymphoma in the United States during 2000 to 2019.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that occurs worldwide. A study of BL in the US National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program during 1973 to 2005 (n = 3043) revealed three age-specific incidence peaks of BL and rates that were rising. We studied BL cases diagnosed in SEER 22 during 2000 to 2019 (n = 11 626) to investigate age-specific BL incidence rates and temporal trends. The age-standardized BL incidence rate was 3.96/million person-years, with a 2.85:1 male-to-female ratio. The BL rate among both Hispanic and White individuals was higher than in Black individuals (4.52, 4.12 vs 3.14). Age-specific BL rates showed peaks during pediatric, adult and elderly years in males and pediatric and elderly peaks in females. Based on 4524 BL cases with HIV status (SEER 13), only one peak in adult males (45 years) was observed. Overall age-standardized BL incidence rates rose 1.2%/year (not significant) up to 2009 then fell significantly by 2.4%/year thereafter. Temporal trends in BL rates during 2000 to 2019 varied with age group as pediatric BL rates rose 1.1%/year, while elderly BL rates fell 1.7%/year and adult BL rates rose 3.4%/year until 2007 before falling 3.1%/year thereafter. Overall survival from BL was 64% at 2 years, being highest in pediatric patients and lowest in Black and elderly individuals vs other subgroups. Survival improved by 20% between 2000 and 2019. Our data suggest that BL age-specific incidence rates are multimodal and that overall BL rates rose up to 2009 and then fell, suggesting changes in etiological factors or diagnosis.

Burkitt lymphoma after solid-organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.

Outcomes of human immunodeficiency virus-associated Burkitt lymphoma and diffuse large B-cell lymphoma treated in Australia: A report from the Australasian Lymphoma Alliance.

Antiretroviral therapy (ART) has improved outcomes for human immunodeficiency virus-associated non-Hodgkin lymphoma (HIV-NHL). This is an analysis of 44 patients with HIV with Burkitt lymphoma (HIV-BL) and diffuse large B-cell lymphoma (HIV-DLBCL) treated in Australia over a 10-year period (2009-2019) during the ART and rituximab era. At HIV-NHL diagnosis, the majority of presenting patients had adequate CD4 counts and undetectable HIV viral load <50 copies/mL. More than 80% of patients received chemotherapy with curative intent, rituximab, and concurrent ART with chemotherapy (immunotherapy). R-CODOX-M/IVAC or R-Hyper-CVAD (55%) were most commonly used in HIV-BL. CHOP (58%) was the most commonly used chemotherapy backbone for HIV-DLBCL, although 45% of patients received more intense chemotherapy regimens. Overall, 93% of patients who received curative therapy completed their intended course. The 2-year progression-free survival (PFS) and overall survival (OS) for the HIV-BL cohort was 67% and 67% respectively. The 2-year PFS and OS for the HIV-DLBCL cohort was 77% and 81% respectively. Treatment related mortality was 5%. In all, 83% of patients achieved a CD4 count of >0.2 ×109 /L 6 months after the end of treatment. Current Australian practice favours the treatment of HIV-BL and HIV-DLBCL similarly to the HIV-negative population with the use of concurrent ART, achieving outcomes comparable to the HIV-negative population.

Epstein-Barr virus and malaria upregulate AID and APOBEC3 enzymes, but only AID seems to play a major mutagenic role in Burkitt lymphoma.

Endemic Burkitt lymphoma (eBL) is characterized by an oncogenic IGH/c-MYC translocation and Epstein-Barr virus (EBV) positivity, and is epidemiologically linked to Plasmodium falciparum malaria. Both EBV and malaria are thought to contribute to eBL by inducing the expression of activation-induced cytidine deaminase (AID), an enzyme involved in the IGH/c-MYC translocation. AID/apolipoprotein B mRNA editing catalytic polypeptide-like (AID/APOBEC) family enzymes have recently emerged as potent mutagenic sources in a variety of cancers, but apart from AID, their involvement in eBL and their regulation by EBV and P. falciparum is unknown. Here, we show that upon inoculation with EBV, human B cells strongly upregulate the expression of enzymatically active APOBEC3B and APOBEC3G. In addition, we found significantly increased levels of APOBEC3A in B cells of malaria patients, which correlated with parasite load. Interestingly, despite the fact that APOBEC3A, APOBEC3B, and APOBEC3G caused c-MYC mutations when overexpressed in HEK293T cells, a mutational enrichment in eBL tumors was only detected in AID motifs. This suggests that even though the EBV- and P. falciparum-directed immune response triggers the expression and activity of several AID/APOBEC members, only the upregulation of AID has oncogenic consequences, while the induction of the APOBEC3 subfamily may primarily have immunoprotective functions.

Inborn errors of human IKAROS: LOF and GOF variants associated with primary immunodeficiency.

IKAROS/IKZF1 plays a pivotal role in lymphocyte differentiation and development. Germline mutations in IKZF1, which have been shown to be associated with primary immunodeficiency, can be classified through four different mechanisms of action depending on the protein expression and its functional defects: haploinsufficiency, dimerization defective, dominant negative, and gain of function. These different mechanisms are associated with variable degrees of susceptibility to infectious diseases, autoimmune disorders, allergic diseases, and malignancies. To date, more than 30 heterozygous IKZF1 germline variants have been reported in patients with primary immunodeficiency. Here we review recent discoveries and clinical/immunological characterization of IKAROS-associated diseases that are linked to different mechanisms of action in IKAROS function.

Epstein-Barr virus reactivation induces MYC-IGH spatial proximity and t(8;14) in B cells.

Burkitt lymphoma (BL) is a B cell malignancy associated with the Epstein-Barr virus (EBV). Most BL cases are characterized by a t(8;14) chromosomal translocation involving the MYC oncogene and the immunoglobulin heavy chain gene (IGH). The role of EBV in promoting this translocation remains largely unknown. Here we provide the experimental evidence that EBV reactivation from latency leads to an increase in the proximity between the MYC and IGH loci, otherwise located far away in the nuclear space both in B-lymphoblastoid cell lines and in patients' B-cells. Specific DNA damage within the MYC locus, followed by the MRE11-dependent DNA repair plays a role in this process. Using a CRISPR/Cas9-based B cell model to induce specific DNA double strand breaks in MYC and IGH loci, we have shown that the MYC-IGH proximity induced by EBV reactivation leads to an increased t(8;14) translocation frequency.