Trimodal age‐specific incidence patterns for Burkitt lymphoma in the United States, 1973–2005

Burkitt lymphoma (BL) is a unique B‐cell non‐Hodgkin lymphoma with 3 established clinical‐epidemiological variants: endemic, sporadic and AIDS‐related BL. BL variants show characteristic dysregulation of MYC gene, but the causes of MYC dysregulation or BL arising at different ages are poorly understood. Therefore, we examined population‐based BL incidence patterns in the United States to determine age‐related risk. BL case and population data were obtained from the NCI's Surveillance, Epidemiology and End Results Databases (1973–2005). Standard cross‐sectional age‐standardized and age‐specific incidence rates were stratified by sex and race and supplemented with age–period–cohort models. We analyzed 3,058 BL cases diagnosed during 1,160,300,297 person‐years of observation. Age‐standardized incidence rates rose 6.8% per year (95% CI 4.5–9.1) for males and 7.1% (95% CI 3.2–11.1) for females during the study period. The rate among males was 3.2 times that among females, and among Whites 1.3 times that among Blacks. Male‐to‐female incidence rate ratios did not differ by race, but were 4.2 for pediatric (0–19 years), 4.1 for adult (20–59 years) and 2.0 for geriatric (≥60 years) BL. Cross‐sectional age‐specific rates showed 2 separate peaks among males and females, near ages 10 and 75 years, and a 3rd peak near age 40 years among males. The tri/bimodal incidence pattern was present in sensitivity analyses excluding registries with many HIV/AIDS cases and in period‐specific, cohort‐specific analyses. To our knowledge, tri/bimodal incidence patterns have not previously been reported for BL. Trimodal/bimodal BL suggests heterogeneity in etiology or biology of BL diagnosed at different ages in males and females. © 2009 UICC.     

In vivo tumor gene delivery using novel peptideticles: pH‐responsive and ligand targeted core–shell nanoassembly

Modulating cancer causing genes with nucleic acid based‐molecules as cutting‐edge approaches need efficient delivery systems to succeed in clinic. Herein, we report design and fabrication of a novel tissue penetrating peptideticle with charge‐structure switching in tumor microenvironment for an effective gene delivery. The comparative in vitro studies indicate that peptideticles identify and bind to tumor endothelial cells and efficiently penetrate into multicellular tumor spheroid. In addition, negatively charged peptideticle at pH 7.4, prevent unwanted interaction while its sharp charge‐structure switching at pH 6.2–6.9 (e.g. in tumor tissue) facilitates malignant cells penetration. More importantly, upon systemic administration into tumor bearing mice, peptideticles effectively localized in tumor tissue and delivered luciferase gene with a 200‐fold higher efficiency compared to their non‐pH‐responsive counterparts. In conclusion, this study presents a robust nanoassembly of safe materials for high efficient tumor gene delivery.     

AID expression in peripheral blood of children living in a malaria holoendemic region is associated with changes in B cell subsets and Epstein‐Barr virus

The development of endemic Burkitt's lymphoma (eBL) is closely associated with Epstein‐Barr virus (EBV) infection and holoendemic malaria infections. The role of EBV in the development of malignancy has been studied in depth, but there is still little known about the mechanisms by which malaria affects Burkitt's lymphomagenesis. Activation induced cytidine deaminase (AID) expression is necessary for the introduction of c‐myc translocations that are characteristic of BL, but a link between AID and EBV or malaria is unclear. To determine whether frequency of malaria exposure leads to increased AID expression in peripheral blood mononuclear cells (PBMC) we examined two cohorts of children in western Kenya with endemic and sporadic malaria transmission dynamics. High frequency of malaria exposure led to increased expression of AID, which coincided with decreases in the IgM⁺ memory B cells. In the children from the malaria endemic region, the presence of a detectible EBV viral load was associated with higher AID expression compared to children with undetectable EBV, but this effect was not seen in children with sporadic exposure to malaria. This study demonstrates that intensity of malaria transmission correlates with AID expression levels in the presence of EBV suggesting that malaria and EBV infection have a synergistic effect on the development of c‐myc translocations and BL.     

Children with endemic Burkitt lymphoma are deficient in EBNA1‐specific IFN‐γ T cell responses

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in equatorial Africa and is linked to Epstein–Barr virus (EBV) and Plasmodium falciparum coinfections early in life. Epstein–Barr nuclear antigen 1 (EBNA1) is the sole viral latent antigen expressed in BL tumors. Loss of EBNA1‐specific immune surveillance could allow eBL emergence. Therefore, EBNA1‐specific T cell responses were analyzed by IFN‐γ ELISPOT in Kenyan children with eBL and compared to healthy children with divergent malaria exposure. Significantly fewer children with eBL, 16% (7/44) had EBNA1‐specific IFN‐γ responses in contrast to healthy children living in a malaria holoendemic area or in an area with sporadic malaria transmission, 67% (40/60) and 72% (43/60) responders, respectively (p < 0.003). Children with eBL maintained IgG₁ dominated antibody responses to EBNA1 similar to healthy children suggesting a selective loss of IFN‐γ secreting EBNA1‐specific T cells in the presence of intact humoral immunity. CD8⁺ T cell responses to EBV lytic and latent antigens not expressed in the tumors were similarly robust in eBL patients compared to healthy children. In addition, CD4⁺ T cell responses to a malaria protein, merozoite surface protein 1, were present in lymphoma patients. This study demonstrates a selective loss of EBNA1‐specific T cell responses in children with eBL and suggests a potential immunotherapeutic target for this EBV‐associated lymphoma. © 2008 Wiley‐Liss, Inc.     

Minireview: invasive fungal infection complicating acute Plasmodium falciparum malaria

Malaria is the most important parasitic infection in people, affecting 5–10% of the world’s population with more than two million deaths a year. Whereas invasive bacterial infections are not uncommon during severe Plasmodium falciparum malaria, only a few cases of opportunistic fungal infections have been reported. Here, we present a fatal case of disseminated hyalohyphomycosis associated with acute P. falciparum malaria in a non‐immune traveller, review the cases reported in the literature and discuss the theoretical foundations for the increased susceptibility of non‐immune individuals with severe P. falciparum malaria to opportunistic fungal infections. Apart from the availability of free iron as sequelae of massive haemolysis, tissue damage, acidosis and measures of advanced life support, patients with complicated P. falciparum malaria also are profoundly immunosuppressed by the organism’s interaction with innate and adaptive host immune mechanisms.     

Distinctions between endemic and sporadic forms of Epstein-Barr virus-positive Burkitt's lymphoma

Tumour cell lines were established in vitro from 16 cases of Epstein-Barr (EB) virus genome-positive Burkitt's lymphoma (BL), 7 of "endemic" origin (i.e. from holoendemic malarial areas of Africa and of New Guinea) and 9 of "sporadic" origin (i.e. from outside such high-incidence areas). All the BL cell lines thus established were monoclonal by immunoglobulin isotype expression and displayed a characteristic chromosomal translocation, t(8:14) or t(8:22), confirming their malignant origin. Clear differences observed between the individual BL cell lines appeared to be related to their endemic or sporadic status. All 7 endemic cell lines began growth as a carpet of single cells, often with small, loose clumps appearing in later passage. Whilst 3 lines of sporadic origin displayed a similar pattern to the above, the majority of sporadic lines grew as large, tight clumps of cells from the first passage onwards. These differences in growth pattern were reflected by differences in cell surface phenotype, as defined in indirect immunofluorescence tests using a panel of monoclonal antibodies (MAbs) specific for B-lineage-associated antigens. BL cell lines could be classified into 3 separate groups on the basis of their reactivity with 6 particular antibodies (MHM6, AC2, Ki-1, Ki-24, J5 and 38.13). All 7 endemic BL cell lines and 2 of the 3 sporadic BL cell lines which began growth as single cells showed a group-I cell-surface phenotype (MHM6, AC2, Ki-1, Ki-24 negative; J5, 38.13 positive) in early passage. In contrast, all 6 sporadic BL cell lines which began growth in large clumps displayed a distinct group-II phenotype (MHM6, AC2, Ki-1 positive/negative; Ki-24, J5, 38.13 positive); in later passage most of these sporadic lines progressed to a group-III phenotype (MHM6, AC2, Ki-1, Ki-24 positive; J5, 38.13 negative) without loss of those immunoglobulin and chromosomal markers identifying the cells' malignant origin. These clear differences between endemic BL cell lines on the one hand and the majority of sporadic BL cell lines on the other suggest that endemic BL arises from a more restricted range of progenitor B cells than does the sporadic form of the disease.     

Conditionally reprogrammed cells (CRC) methodology does not allow the in vitro expansion of patient‐derived primary and metastatic lung cancer cells

Availability of tumor and non‐tumor patient‐derived models would promote the development of more effective therapeutics for non‐small cell lung cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient‐derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non‐tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non‐malignant tissues with extraordinary high efficiency. Tumor cells were tracked in vitro through tumorigenicity assay, monitoring of tumor‐specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies‐derived cultures rapidly lost patient‐specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient‐derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non‐malignant lung epithelial stem cells from either tumor or non‐tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor‐derived CRC cultures are composed of (non‐tumoral) airway basal cells.     

Gastric microbiota features associated with cancer risk factors and clinical outcomes: A pilot study in gastric cardia cancer patients from Shanxi,China

Little is known about the link between gastric microbiota and the epidemiology of gastric cancer. In order to determine the epidemiologic and clinical relevance of gastric microbiota, we used 16 S ribosomal RNA gene sequencing analysis to characterize the composition and structure of the gastric microbial community of 80 paired samples (non‐malignant and matched tumor tissues) from gastric cardia adenocarcinoma (GCA) patients in Shanxi, China. We also used PICRUSt to predict microbial functional profiles. Compared to patients without family history of upper gastrointestinal (UGI) cancer in the non‐malignant gastric tissue microbiota, patients with family history of UGI cancer had higher Helicobacter pylori (Hp) relative abundance (median: 0.83 vs. 0.38, p = 0.01) and lower alpha diversity (median observed species: 51 vs. 85, p = 0.01). Patients with higher (vs. lower) tumor grade had higher Hp relative abundance (0.73 vs. 0.18, p = 0.03), lower alpha diversity (observed species, 66 vs. 89, p = 0.01), altered beta diversity (weighted UniFrac, p = 0.002) and significant alterations in relative abundance of five KEGG functional modules in non‐malignant gastric tissue microbiota. Patients without metastases had higher relative abundance of Lactobacillales than patients with metastases (0.05 vs. 0.01, p = 0.04) in non‐malignant gastric tissue microbiota. These associations were observed in non‐malignant tissues but not in tumor tissues. In conclusion, this study showed a link of gastric microbiota to a major gastric cancer risk factor and clinical features in GCA patients from Shanxi, China. Studies with both healthy controls and gastric cardia and noncardia cancer cases across different populations are needed to further examine the association between gastric cancer and the microbiota.     

Epigenetic reprogramming reverses the malignant epigenotype of the MMP/TIMP axis genes in tumor cells

Cancer progression is characterized by extensive tumor invasion into the surrounding extracellular matrix (ECM) and migration to metastatic sites. The increased proteolytic degradation of the ECM during tumor invasion is directly dependent on the activity of matrix metalloproteinases (MMPs), counter‐balanced by tissue inhibitors of matrix metalloproteinases (TIMPs). In this study, we found that unbalanced expression of MMP/TIMP axis genes in tumors was correlated with aberrant epigenotypes in the various gene promoters. The malignant epigenotypes could be therapeutically corrected by a simple defined factor‐mediated reprogramming approach. Correction of the abnormal epigenotypes by nuclear remodeling leads to a rebalance in the gene expression profile, an alteration in tumor cell morphology, attenuation of tumor cell migration and invasion in vitro, and reduced tumorigenicity in nude mice. We further identified the downregulation of the MKK‐p38 MAPK signal pathway as an important underlying mechanism for reduced tumorigenicity in this epigenetic reprogramming model. These data demonstrate that the malignant phenotypes seen in cancer can be corrected by a nuclear remodeling mechanism, thus highlighting a novel non‐chemotherapeutic, non‐radiotherapeutic approach for the treatment of cancer.     

Etiology of endemic Burkitt's lymphoma

There is a considerable volume of evidence linking Epstein-Barr virus (EBV) etiologically with Burkitt's lymphoma (BL). BL has satisfied the Henle-Koch criteria. Thus BL patients have significantly higher EBV antibody titres than normal or tumour controls. EBV DNA and EBV-determined nuclear antigen (EBNA) have been demonstrated in a high proportion (greater than 90%) of endemic BL tissues. EBV can transform and immortalize human B-lymphocytes and is known to cause lymphoreticular tumours in New World monkeys. The fact that endemic BL is almost invariably associated with EBV while this is rarely true of the non-endemic form suggests disease heterogeneity in spite of morphological uniformity. The role of malaria as a co-factor in causing immunosuppression and promoting proliferation of EBV-transformed cell is discussed. The identification of specific chromosomal abnormalities in both endemic and non-endemic BL underscores the importance of a suitable genetic background.     

Human papillomavirus capsids preferentially bind and infect tumor cells

We previously determined that human papillomavirus (HPV) virus‐like particles (VLPs) and pseudovirions (PsV) did not, respectively, bind to or infect intact epithelium of the cervicovaginal tract. However, they strongly bound heparan sulfate proteoglycans (HSPG) on the basement membrane of disrupted epithelium and infected the keratinocytes that subsequently entered the disrupted site. We here report that HPV capsids (VLP and PsV) have the same restricted tropism for a wide variety of disrupted epithelial and mesothelial tissues, whereas intact tissues remain resistant to binding. However, the HPV capsids directly bind and infect most tumor‐derived cell lines in vitro and have analogous tumor‐specific properties in vivo, after local or intravenous injection, using orthotopic models for human ovarian and lung cancer, respectively. The pseudovirions also specifically infected implanted primary human ovarian tumors. Heparin and ι‐carrageenan blocked binding and infection of all tumor lines tested, implying that tumor cell binding is HSPG‐dependent. A survey using a panel of modified heparins indicates that N‐sulfation and, to a lesser degree, O‐6 sulfation of the surface HSPG on the tumors are important for HPV binding. Therefore, it appears that tumor cells consistently evolve HSPG modification patterns that mimic the pattern normally found on the basement membrane but not on the apical surfaces of normal epithelial or mesothelial cells. Consequently, appropriately modified HPV VLPs and/or PsV could be useful reagents to detect and potentially treat a remarkably broad spectrum of cancers.     

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.     

Burkitt lymphoma versus diffuse large B‐cell lymphoma: a practical approach

Burkitt Lymphoma (BL) is listed in the World Health Organization (WHO) classification of lymphoid tumours as an “aggressive B‐cell non‐Hodgkin's lymphoma”, characterized by a high degree of proliferation of the malignant cells and deregulation of the c‐MYC gene. The main diagnostic challenge in BL is to distinguish it from diffuse large B‐cell lymphoma (DLBCL). While in children BL and DLBCL types probably do not differ clinically, and the differential diagnosis between BL and DLBCL may theoretically appear clear‐cut, in adults daily practice shows the existence of cases that have morphological features, immunophenotypic and cytogenetics intermediate between DLBCL and BL, and cannot be classified with certainty in these categories. Distinguishing between BL and DLBCL is critical, as the two diseases require different management. This review summarizes the current practical approach, including the use of a large panel of antibodies, and cytogenetic and molecular diagnostic techniques, to distinguish between BL, DLBCL and the provisional category of “B‐cell lymphoma, unclassificable, with features intermediate between diffuse large B‐cell lymphoma and Burkitt lymphoma”, now listed in the updated WHO classification. Copyright © 2009 John Wiley & Sons, Ltd.     

Different DNA damage and cell cycle checkpoint control in low- and high-risk human papillomavirus infections of the vulva

Human papillomavirus (HPV) infections may result in benign hyperplasia, caused by low‐risk HPV types, or (pre)malignant lesions caused by high‐risk HPV types. The molecular basis of this difference in malignant potential is not completely understood. Here, we performed gene profiling of different HPV infected vulvar tissues (condylomata acuminata (n = 5), usual type vulvar intraepithelial neoplasia (uVIN) (n = 9)) and control samples (n = 14) using Affymetrix Human U133A plus 2 GeneChips. Data were analyzed using OmniViz®, Partek® and Ingenuity® Software. Results were validated by real‐time RT‐PCR and immunostaining. Although similarities were observed between gene expression profiles of low‐ and high‐risk HPV infected tissues (e.g., absence of estrogen receptor in condylomata and uVIN), high‐risk HPV infected tissues showed more proliferation and displayed more DNA damage than tissues infected with low‐risk HPV. These observations were confirmed by differential regulation of cell cycle checkpoints and by increased expression of DNA damage‐biomarkers p53 and γH2AX. Furthermore, FANCA, FANCD2, BRCA1 and RAD51, key players in the DNA damage response, were significantly upregulated (p < 0.05). In addition, we compared our results with publicly available gene expression profiles of various other HPV‐induced cancers (vulva, cervix and head‐and‐neck). This showed p16^INK4a was the most significant marker to detect a high‐risk HPV infection, but no other markers could be found. In conclusion, this study provides insight into the molecular basis of low‐ and high‐risk HPV infections and indicates two main pathways (cell cycle and DNA damage response) that are much stronger affected by high‐risk HPV as compared to low‐risk HPV.     

Ethnic and racial differences in patients with Ewing sarcoma

BACKGROUND:

Ewing sarcoma (ES) was a malignant tumor of bone or soft tissue. One of the few risk factors for developing ES is race, with a higher incidence noted in populations of European rather than African or Asian ancestry. The goal of the current study was to evaluate racial and ethnic differences in presentation and overall survival (OS) among patients diagnosed with ES before age 40 years.

METHODS:

Data from the Surveillance, Epidemiology, and End Results database identified 1715 patients aged <40 years who were diagnosed with ES between 1973 and 2005. Racial and ethnic group differences were compared using chi‐square tests. OS was estimated by Kaplan‐Meier analysis and compared using log‐rank tests and Cox models.

RESULTS:

Black patients had significantly more soft‐tissue tumors compared with white non‐Hispanic patients (P <.0001). Asian and white Hispanic patients were found to have an intermediate frequency of soft‐tissue tumors that also differed from white non‐Hispanic patients (P <.0001). White Hispanic patients presented with a higher proportion of larger tumors compared with white non‐Hispanic patients (P = .042). Black patients tended to be older than white non‐Hispanic patients (P = .012). Sex, frequency of pelvic tumors, and metastatic status did not appear to differ by ethnicity or race. OS was found to differ according to race and ethnicity. Even after controlling for known confounders, OS was significantly worse for black, Asian, and white Hispanic patients compared with white non‐Hispanic patients (P = .0031, P = .0182, and P = .0051, respectively).

CONCLUSIONS:

Ethnic and racial differences in characteristics and outcomes of patients with ES do exist. Understanding the etiology of these differences will require further study. Cancer 2010. © 2010 American Cancer Society.     

Genome‐wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS‐specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole‐genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA). Genes or regions frequently targeted by SCNAs were identified. Breakage analysis revealed OS specific unstable regions in which well‐known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2 and LSAMP are located. Certain genomic features, such as transposable elements and non‐B DNA‐forming motifs were found to be significantly enriched in the vicinity of chromosomal breakage sites. A complex breakage pattern—chromothripsis—has been suggested as a widespread phenomenon in OS. It was further demonstrated that hyperploidy and in particular chromothripsis were strongly correlated with OS patient clinical outcome. The revealed OS‐specific fragility pattern provides novel clues for understanding the biology of OS.     

A study on sequence variations in pre‐S/surface,X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non‐B,non‐C hepatocellular carcinoma patients in Taiwan

This study was to investigate the clinical significance and virologic factors of occult hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) patients without hepatitis B surface antigen (HBsAg) or anti‐hepatitis C virus (non‐B, non‐C) in Taiwan. Serum HBV DNA (occult HBV) was detected in 90 of 222 non‐B, non‐C HCC patients and 24 of 300 non‐B, non‐C controls without HCC. Of 90 occult HBV‐infected HCC patients, the sequences of HBV pre‐S/surface, X and enhancer II/core promoter/precore genes were analyzed from 40 patients. Direct sequencing of such genes was also performed in 24 non‐B, non‐C controls without HCC and 40 HBsAg‐positive HCC controls. Compared with non‐B, non‐C controls without HCC, non‐B, non‐C subjects with HCC had significantly higher prevalence of occult HBV (p < 0.0001). Moreover, M1I and Q2K in pre‐S2 gene and G1721A were more common in occult HBV‐infected patients with HCC than in those without HCC. Compared with the HBsAg‐positive HCC controls, occult HBV‐infected HCC patients had higher frequencies of M1I and Q2K in pre‐S2 gene, G185R and S210N in surface gene, A36T and A44L in X gene, and G1721A in enhancer II gene, and had lower rates of pre‐S deletions and A1762T/G1764A, A1846T, G1896A and G1899A in core promoter/precore genes. Multivariate analysis showed Q2K in pre‐S2 gene, G1721A and A1846T were independent factors for occult HBV‐infected HCC. Our study suggested that the virological factors of HBV related to HCC were different between occult HBV‐infected and HBsAg‐positive patients. The G1721A, M1I and Q2K in pre‐S2 gene may be useful viral markers for HCC in occult HBV carriers. © 2009 UICC     

Loss of cooperativity of secreted CD40L and increased dose–response to IL4 on CLL cell viability correlates with enhanced activation of NF‐kB and STAT6

Chronic lymphocytic leukemia (CLL) cells fail to enter apoptosis in vivo as opposed to their non‐malignant B‐lymphocyte counterparts. The ability of CLL cells to escape apoptosis is highly dependent on their microenvironment. Compared to non‐malignant B cells, CLL cells are more responsive to complex stimuli that can be reproduced in vitro by the addition of cytokines. To understand the molecular mechanism of the environment‐dependent anti‐apoptotic signaling circuitry of CLL cells, we quantified the effect of the SDF‐1, BAFF, APRIL, anti‐IgM, interleukin‐4 (IL4) and secreted CD40L (sCD40L) on the survival of in vitro cultured CLL cells and found IL4 and sCD40L to be most efficient in rescuing CLL cells from apoptosis. In quantitative dose–response experiments using cell survival as readout, the binding affinity of IL4 to its receptor was similar between malignant and non‐malignant cells. However, the downstream signaling in terms of the amount of STAT6 and its degree of phosphorylation was highly stimulated in CLL cells. In contrast, the response to sCD40L showed a loss of cooperative binding in CLL cells but displayed a largely increased ligand binding affinity. Although a high‐throughput microscopy analysis did not reveal a significant difference in the spatial CD40 receptor organization, the downstream signaling showed an enhanced activation of the NF‐kB pathway in the malignant cells. Thus, we propose that the anti‐apoptotic phenotype of CLL involves a sensitized response for IL4 dependent STAT6 phosphorylation, and an activation of NF‐kB signaling due to an increased affinity of sCD40L to its receptor.     

The distribution of non-Burkitt, non-Hodgkin's lymphomas in Uganda in relation to malarial endemicity

Biopsies of malignant lymphomas collected from all districts of Uganda, filed in the Kampala Cancer Registry for the 8-year period 1966-1973, were reviewed. This review confirmed a relatively low frequency of follicle-centre-cell lymphomas with a follicular growth pattern and the geographical co-distribution between malaria and Burkitt's lymphoma (BL). It also showed a similar, though less marked, association between non-Burkitt, non-Hodgkin's lymphoma (NBNHL) and malarial endemicity, and a correlation in the regional incidence between BL and NBNHL. In both comparisons, these associations were strong for high-grade lymphomas and weak for low-grade neoplasms. BL and other NHL may therefore share, to a varying degree, some common pathogenesis. The excess in frequency of NBNHL of high-grade malignancy in malarial endemic areas appears to be in contrast to Western countries where most non-Hodgkin's lymphomas are of low-grade malignancy.