A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin

Relapsed or refractory Burkitt''s lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt''s lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt''s lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.     

Bortezomib inhibits Burkitt's lymphoma cell proliferation by downregulating sumoylated hnRNP K and c-Myc expression

Bortezomib (Velcal) was the first proteasome inhibitor to be approved by the US Food and Drug Administration to treat patients with relapsed/refractory multiple myelomas. Previous studies have demonstrated that bortezomib inhibits tumor cell proliferation and induces apoptosis by blocking the nuclear factor (NF)-κB pathway. However, the exact mechanism by which bortezomib induces cancer cell apoptosis is still not well understood. In this study, we found that bortezomib significantly inhibited cell proliferation in both human Burkitt''s lymphoma CA46 and Daudi cells. Through proteomic analysis, we found that bortezomib treatment changed the expression of various proteins in distinct functional categories including unfolding protein response (UPS), RNA processing, protein targeting and biosynthesis, apoptosis, and signal transduction. Among the proteins with altered expression, hnRNP K, hnRNP H, Hsp90α, Grp78, and Hsp7C were common to both Daudi and CA46 cells. Interestingly, bortezomib treatment downregulated the expression of high-molecular-weight (HMw) hnRNP K and c-Myc but upregulated the expression of low-molecular-weight (LMw) hnRNP K. Moreover, cell proliferation was significantly correlated with high expression of HMw hnRNP K and c-Myc. HMw and LMw hnRNP K were identified as sumoylated and desumoylated hnRNP K, respectively. Using transient transfection, we found that sumoylated hnRNP K increased c-Myc expression at the translational level and contributed to cell proliferation, and that Lys422 of hnRNP K is the candidate sumoylated residue. Our results suggest that besides inhibiting the ubiquitin-proteasome pathway, bortezomib may inhibit cell proliferation by downregulating sumoylated hnRNP K and c-Myc expression in Burkitt''s lymphoma cells.     

Survival predictors of Burkitt's lymphoma in children,adults and elderly in the United States during 2000–2013

Burkitt's Lymphoma (BL) has three peaks of occurrence, in children, adults and elderly, at 10, 40 and 70 years respectively. To the best of our knowledge, no study has been conducted to assess predictors of survival in the three age groups. We hypothesized that survival predictors may differ by age group. We, therefore, sought to determine survival predictors for BL in these three groups: children (<15 years of age), adults (40–70 years of age) and elderly (>70 years of age). Using the Surveillance, Epidemiology, and End Results (SEER) database covering the years 2000‐2013, we identified 797 children, 1,994 adults and 757 elderly patients newly diagnosed with BL. We used adjusted Cox proportional hazards regression models to determine prognostic factors for survival for each age group. Five‐year relative survival in BL for children, adults and elderly were 90.4, 47.8 and 28.9%, respectively. Having at least Stage II disease and multiple primaries were associated with higher mortality in the elderly group. In adults, multiple primaries, Stage III or IV disease, African American race and bone marrow primary were associated with increased mortality whereas Stage IV disease and multiple primaries were associated with worse outcome in children. These findings demonstrate commonalities and differences in predictors of survival that may have implications for management of BL patients.     

Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines

Burkitt''s lymphoma (BL) is a highly aggressive form of B-cell non-Hodgkin''s lymphoma. The clinical outcome in children with BL has improved over the last years but the prognosis for adults is still poor, highlighting the need for novel treatment strategies. Here, we report that the combinational treatment with the Smac mimetic BV6 and TRAIL triggers necroptosis in BL when caspases are blocked by zVAD.fmk (TBZ treatment). The sensitivity of BL cells to TBZ correlates with MLKL expression. We demonstrate that necroptotic signaling critically depends on MLKL, since siRNA-induced knockdown and CRISPR/Cas9-mediated knockout of MLKL profoundly protect BL cells from TBZ-induced necroptosis. Conversely, MLKL overexpression in cell lines expressing low levels of MLKL leads to necroptosis induction, which can be rescued by pharmacological inhibitors, highlighting the important role of MLKL for necroptosis execution. Importantly, the methylation status analysis of the MLKL promoter reveals a correlation between methylation and MLKL expression. Thus, MLKL is epigenetically regulated in BL and might serve as a prognostic marker for treatment success of necroptosis-based therapies. These findings have crucial implications for the development of new treatment options for BL.     

Hyperfractionated radiation therapy in Burkitt's lymphoma: a reconsideration aspect

Burkitt's lymphoma (BL) is an aggressive non‐Hodgkin's B‐cell lymphoma with an extremely short doubling time that often presents in extra nodal sites or as an acute leukaemia. Nowadays, with the rapid response to chemotherapy and the diffuse nature of BL, there is no established role for radiation therapy (RT) even in localized disease. Regarding the relapsed/refractory BL, the treatment recommendations remain undefined. We present a 56‐year‐old woman, diagnosed with BL refractory to 6 cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), who had disease progression on R‐DHAP (rituximab, dexamethasone, high dose cytarabine and cisplatin) with intrathecal methotrexate, then a partial response on RICE (rituximab, ifosfamide, carboplatin and etoposide). Patient received high dose chemotherapy and autologous haematopoietic stem cell transplantation. Then, she was treated with hyperfractionated involved‐field RT regimen. Currently, the patient remains disease free for around 2 years after remission. We acknowledge that RT is not a standard treatment of BL, especially in patients who attain complete response (CR) after first‐line multi‐agent chemotherapy or even in those who have a CR after second‐line chemotherapy pre‐transplant. Yet, the use of a superfractionated regimen of consolidative radiation could be justified in the treatment of recurrent/refractory localized BL who do not achieve a CR even with second‐line salvage chemotherapy. Radiation therapy in this context, given that it is a well‐tolerated treatment, is a modality worthy of being re‐considered in relapsed/refractory BL. Copyright © 2016 John Wiley & Sons, Ltd.     

Dok1 expression and mutation in Burkitt's lymphoma cell lines

Dok1 is an adaptor tyrosine kinase substrate with tumor-suppressive activity. The gene encoding Dok1 maps to human chromosome 2p13, which is frequently rearranged in human tumors. We have previously reported a frameshift mutation of this gene and the down-regulation of its expression in chronic lymphocytic leukemia. In this study, we have determined the expression levels of Dok1 in Burkitt's lymphoma (BL) cell lines, lymphoblastoid cell lines from patients with X-linked lymphoproliferative (XLP-LCL), or from control healthy donors. We have also screened for Dok1 gene mutations by heteroduplex analysis and direct sequencing. Dok1 expression was down-regulated in all BL and XLP-LCL cell lines in comparison to the control cells. No Dok1 mutation or polymorphism was found in the coding region of Dok1 in the three types of cells. However, DNA sequence analysis revealed the presence of four nucleotide changes in Dok1 gene, T(90172)C (intron 1), C(89487)T and (89433)InsCTCT (intron 2), and A(87714)G (3' UTR). T(90172)C and (89433)InsCTCT that were detected in about 7% of BL, 9% of XLP-LCL and 4% of normal samples may represent a common polymorphism. C(89487)T and A(87714)G changes were detected in 9 and 6% of analyzed BL lines, respectively, but never in the control and XLP-LCL cells, indicating that these nucleotide substitution occurred during tumor development. Interestingly, the C(89487)T variant is associated with a significantly lower level of Dok1 expression compared to the control samples. A positive association was also found between the presence of EBV in BL and the Dok1 genetic variation. Our data show that Dok1 expression and structure are affected in a subset of Burkitt's lymphoma samples, suggesting its possible role in this type of cancer.     

Expression of differentiation and adhesion molecules in sporadic Burkitt's lymphoma

The phenotypic features of 44 cases of sporadic Burkitt's lymphoma (BL) were investigated by monoclonal antibodies (MoAbs). The majority of cases were positive for HLA-DR (97 per cent), CD19 (100 per cent), CD20 (92 per cent) and CD37 (83 per cent) pan-B markers, in accordance with the B-cell derivation of the tumour; the B-cell restricted markers CD21, CD22 and FMC7 reacted with 28 per cent, 66 per cent and 75 per cent of cases, respectively. Of the mantle zone B-cell specific MoAbs, CD1c was always negative, whereas CD23 and 2.7 were positive with one and two cases, respectively. CD39 was weakly reactive on two specimens, one of which was CD23+. The germinal centre specific MoAbs CD10 and CD77 (Burkitt's lymphoma antigen) displayed a heterogeneous pattern of reactivity and allowed to identify 4 subgroups: CD10+/CD77+ (44 per cent), CD10+/CD77- (15 per cent), CD10-/CD77+ (36 per cent) and CD10-/CD77- (5 per cent). Of 15 cases tested for the expression of CD11a and CD18 lymphocyte-function-associated (LFA-1) antigens and their ligand ICAM-1 (CD54), seven were positive and six negative for the three markers, while the other two cases expressed alternatively the two molecules. Analysis of the putative normal BL cell counterpart, identified with the CD77 marker in normal lymphoid tissues, showed that all CD77+ B-cells were constitutively CD11a+/CD18+, suggesting that BLs are likely to arise from a LFA-1 positive B-cell and may down-regulate these molecules during neoplastic transformation.     

Risk of lymphoma subtypes after solid organ transplantation in the United States

Background:

Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes.

Methods:

We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation.

Results:

The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt''s lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys.

Conclusion:

Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.     

Chromosomal abnormalities in adult non-endemic Burkitt's lymphoma and leukemia: 22 new reports and a review of 148 cases from the literature

Tumour cell karyotypes from patients with Burkitt lymphoma (BL) or Burkitt's type leukemia (ALL3) were studied for correlation with survival, bone marrow and cerebral spinal fluid involvement (CSF), human immunodeficiency virus (HIV) serology, and for recurrent cytogenetic abnormalities. The records of 22 patients with BL from our institution and of 148 cases of BL and ALL3 reported in the literature with karyotypes were evaluated for clinical and cytological features. Overall survival was only 28 per cent and 88 per cent of deaths occurred within the first nine months after diagnosis. Those who survived at least 18 months were unlikely to relapse. Age and gender did not significantly affect survival. Patients presenting with advanced Ann Arbor stage, bone marrow or CSF involvement had lower survival rates. The association of translocations involving chromosome band 8q24 with this disease is confirmed. Sixty-two per cent of karyotypes had t(8;14)(q24;q32) translocations; the recognized variant translocations t(8;22)(q24;q11) and t(2;8)(p12;q24) affected 12 per cent and 9 per cent respectively. Seventeen per cent had abnormal karyotypes but no classic translocation. Patients with variant translocations had the poorest survival rates, and those with the classic t(8;14)(q24;q32) did the best. Despite a small sample size, the variant translocation t(8;22)(q24;q11) appeared to occur at an increased frequency in the patients with AIDS. In the entire group, recurrent involvement of chromosome regions 1q2, 6q11-14 and 17p1 suggests that alteration of genes at these loci, B Cell Growth Factor (BCGF) at 1q2 and p53 on 17p, may contribute to the development and progression of this tumour. Similarly, the frequent trisomies of chromosomes 7, 8, 12 and 18 may indicate an effect on tumour cell growth due to increased gene dosage. Trisomy 12 was found in eight tumours, five from patients with AIDS, suggesting that chromosome 12 has a site or gene whose allelic dosage is selected for in AIDS related lymphoma cells. Cytogenetic studies of adult Burkitt lymphoma and leukemia suggest several likely loci for gene alterations that in conjunction with myc translocations can lead to tumorigenesis.     

Geographic variation in Epstein-Barr virus-associated Burkitt's lymphoma in children from Brazil

In developing countries, BL has a strong association with EBV infection during childhood. In South America, the data have shown an EBV association intermediate between that reported in the United States (30%) and that in equatorial Africa (95%). Early age at EBV infection and lower socioeconomic status have been related to increased EBV-associated BL in developing countries. In Brazil, there are not enough data on childhood BL related to EBV infection. Our aim was to evaluate the clinicopathologic features and EBV association of 44 children with NHL from the state of Rio de Janeiro, situated in the southeast of Brazil. EBV was detected using RNA in situ hybridization in 36 biopsy specimens. DNA from fresh tumor samples and from paraffin-embedded tissues of patients were analyzed by PCR, in which the first reaction included primers for an EBNA-2 common region while the nested reaction amplified the region discriminating between EBV types 1 and 2 in separate reactions. EBV was detected in 21 of 29 BLs (72%), and type 1 virus infected the majority of EBV-positive BLs (18/21). There was a trend for younger age in children with EBV-positive BL compared to EBV-negative BL (median age 4 compared to 6 years, respectively; p = 0.056). Our study confirmed that in the southeast of Brazil BL had an intermediate association with EBV. A higher rate of EBV-associated BL was described in the northeast of Brazil. These differences are probably related to regional socioeconomic status. In conclusion, our study suggests that early infection with EBV in the background of a low socioeconomic condition associated with other environmental factors could contribute to BL in Brazil.     

Accumulation of p53 protein correlates with tumour proliferative activity in EBV positive Burkitt's lymphoma.

p53 tumour suppressor gene is often found mutated in Burkitt's lymphoma (BL) cell lines and tumours. We analysed 35 BL tumours for the accumulation of p53 protein, and correlated the results with DNA flow cytometric data on the proliferative activity (SPF), and data on the presence or absence of Epstein-Barr virus (EBV) DNA. More than one-third (37 per cent) of the tumours showed accumulation of p53, which was considered to be consistent with mutation of the p53 gene. Tumours that were positive both for EBV DNA and p53 had significantly higher mean SPF than corresponding EBV DNA negative and/or p53 negative tumours. The proportions of tumour cells with accumulation of p53 appeared to correlate with tumour SPF only in EBV DNA positive BLs. However, there was no apparent association between accumulation of p53 and the presence or absence of EBV DNA. These findings are suggestive of multiple pathways in BL tumour progression.     

Spatial clustering of endemic Burkitt's lymphoma in high-risk regions of Kenya

Endemic Burkitt's lymphoma (eBL), the most common childhood cancer in sub-Saharan Africa, occurs at a high incidence in western Kenya, a region that also experiences holoendemic malaria. Holoendemic malaria has been identified as a co-factor in the etiology of this cancer. We hypothesized that eBL may cluster spatially within this region. Medical records for all eBL cases diagnosed from 1999 through 2004 at Nyanza Provincial General Hospital were reviewed for case residential information to examine this hypothesis. Two cluster detection methods, Anselin's Local Moran test for spatial autocorrelation and a spatial scan test statistic, were applied to this residential data to determine whether statistically significant high- and low-risk areas were present in the Province. During the 6-year study period, 272 children were diagnosed with eBL, with an average annual incidence of 2.15 cases per 100,000 children. Using Empirical Bayes smoothed rates, the Local Moran test identified 1 large multi-centered area of low eBL risk (p-values < 0.01) and 2 significant multi-centered clusters of high eBL risk (p-values < 0.001). The spatial scan detected 3 small independent low-risk areas (p-values < 0.02) and 2 high-risk clusters (p-values = 0.001), both similar in location to those identified from the Local Moran analysis. Significant spatial clustering of elevated eBL risk in high-malaria transmission regions and of reduced incidence where malaria is infrequent suggests that malaria plays a role in the complex eBL etiology, but that additional factors are also likely involved.     

TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms

Enhanced proliferative signaling and loss of cell cycle regulation are essential for cancer progression. Increased mitogenic signaling through activation of the mTOR pathway, coupled with deregulation of the Cyclin D/retinoblastoma (Rb) pathway is a common feature of lymphoid malignancies, including plasmacytoma (PCT), multiple myeloma (MM), Burkitt''s lymphoma (BL), and mantle cell lymphoma (MCL). Here we evaluate the synergy of pharmacologically affecting both of these critical pathways using the mTOR inhibitor sirolimus and the histone deacetylase inhibitor entinostat. A dose‐matrix screening approach found this combination to be highly active and synergistic in a panel of genetically diverse human MM cell lines. Synergy and activity was observed in mouse PCT and human BL and MCL cell lines tested in vitro, as well as in freshly isolated primary MM patient samples tested ex vivo. This combination had minimal effects on healthy donor cells and retained activity when tested in a co‐culture system simulating the protective interaction of cancer cells with the tumor microenvironment. Combining sirolimus with entinostat enhanced cell cycle arrest and apoptosis. At the molecular level, entinostat increased the expression of cell cycle negative regulators including CDKN1A (p21) and CDKN2A (p16), while the combination decreased critical growth and survival effectors including Cyclin D, BCL‐XL, BIRC5, and activated MAPK.     

Dose‐intensive chemotherapy including rituximab in Burkitt's leukemia or lymphoma regardless of human immunodeficiency virus infection status

BACKGROUND:

The use of rituximab together with intensive chemotherapy in Burkitt's lymphoma or leukemia (BL) has been scarcely explored. This study prospectively evaluated and compared the outcome and toxicity of human immunodeficiency virus (HIV)‐positive and HIV‐negative patients with BL who were treated in an intensive immunochemotherapy‐based and age‐adapted trial.

METHODS:

A total of 118 adult patients (80 HIV‐negative and 38 HIV‐positive) aged 15 to 83 years were treated with 4 (nonbulky stages I‐II) or 6 (stages II bulky, III‐IV) cycles of intensive chemotherapy combined with rituximab. Reduction in chemotherapy doses and modification of the cycle schedules was performed in patients older than 55 years.

RESULTS:

The clinical characteristics of HIV‐positive patients were comparable with those who were HIV‐negative. Complete remission rates were 82% and 87%, respectively, and 9 patients died in induction, 9 died in remission, and 7 relapsed. After a median follow‐up of 2.5 years, nonsignificant differences were observed in the 4‐year disease‐free survival and overall survival (OS) probabilities (77% and 63% for HIV‐positive and 80% and 78% for HIV‐negative patients, respectively). Young HIV‐infected patients presented higher incidences of grade 3 or 4 mucositis and severe infectious episodes. Poor general status and bone marrow involvement, but not advanced age, were associated with a shorter OS, allowing the definition of 3 prognostic groups, with the OS ranging from 50% to 92%.

CONCLUSIONS:

Age‐adapted intensive immunochemotherapy is highly effective in both HIV‐negative and HIV‐positive patients, with a higher toxicity in the latter group. Poor general status and bone marrow involvement had a negative impact on survival. Cancer 2013. © 2013 American Cancer Society.     

Phase II study of docetaxel in patients with relapsed or refractory malignant lymphoma

We report the activity and toxicity of docetaxel in 12 evaluable heavily pretreated patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease. In all, 42% achieved a partial response, 25% achieved stable disease. Median duration of response was 16 (10-21) weeks. The median overall survival was 70 (9-178) weeks and for responders it was 120 (22-178) weeks. One patient developed one episode of neutropenic sepsis. Docetaxel has limited activity in this group of patients.     

Comparison of the distribution of non-AIDS Kaposi's sarcoma and non-Hodgkin's lymphoma in Europe.

To evaluate whether some form of mild immunosuppression may influence the geographical distribution of non-AIDS Kaposi's sarcoma (KS), we correlated incidence rates of KS and non-Hodgkin's lymphoma in individuals aged 60 or more in 18 European countries and Israel. Significant positive correlations emerged but, within highest risk countries (i.e. Italy and Israel), internal correlations were inconsistent.     

Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster

Although the anti-CD20 antibody Rituximab has revolutionized the treatment of Non-Hodgkin Lymphoma (NHL), resistance to treatment still existed. Thus, strategies for suppressing Rituximab-resistant NHLs are urgently needed. Here, an anti-CD20 nanocluster (ACNC) is successfully constructed from its type I and type II mAb (Rituximab and 11B8). These distinct anti-CD20 mAbs are mass grafted to a short chain polymer (polyethylenimine). Compared with parental Rituximab and 11B8, the ACNC had a reduced “off-rate”. Importantly, ACNC efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspase-dependent apoptosis and lysosome-mediated programmed cell death (PCD). This may help explain why ACNC is effective in suppressing rituximab-resistant lymphoma while Rituximab and 11B8 are not. Additionally, ACNC experienced low clearance from peripheral blood and high intratumor accumulation. This improved pharmacokinetics is attributed to the antibody-antigen reaction (active targeting) and enhanced permeability and retention (ERP) effect (passive targeting). This study suggested that ACNC might be a promising therapeutic agent for treatment of rituximab-resistant lymphomas.     

Malaria,Epstein–Barr virus infection and the pathogenesis of Burkitt's lymphoma

A geographical and causal connection has long been recognized between malaria, Epstein–Barr virus (EBV) infection and Burkitt's lymphoma (BL), but the underlying mechanisms remain obscure. Potential clues are that the malaria parasite Plasmodium falciparum selectively absorbs vitamin A from the host and depends on it for its biological activities; secondly, alterations in vitamin A (retinoid) metabolism have been implicated in many forms of cancer, including BL. The first author has proposed that the merozoite‐stage malaria parasite, emerging from the liver, uses its absorbed vitamin A as a cell membrane destabilizer to invade the red blood cells, causing anemia and other signs and symptoms of the disease as manifestations of an endogenous form of hypervitaminosis A (Mawson AR, Path Global Health 2013;107(3):122–9). Repeated episodes of malaria would therefore be expected to expose the tissues of affected individuals to potentially toxic doses of vitamin A. It is proposed that such episodes activate latent EBV infection, which in turn activates retinoid‐responsive genes. Expression of these genes enhances viral replication and induces germinal center (GC) B cell expansion, activation‐induced cytidine deaminase (AID) expression, and c‐myc translocation, which in turn predisposes to BL. Thus, an endogenous form of retinoid toxicity related to malaria infection may be the common factor linking frequent malaria, EBV infection and BL, whereby prolonged exposure of lymphatic tissues to high concentrations of retinoids may combine to induce B‐cell translocation and increase the risk of Burkitt's lymphoma.