Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration

Abstract

Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. OfCS is absent from other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor-site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue, encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy.

Associations between IgG reactivity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens and Burkitt lymphoma in Ghana and Uganda case-control studies

“…Counterintuitively, compared to controls, serum from eBL cases in both Ghana and Uganda showed lower breadth and intensity of IgG reactivity to Pf EMP1 CIDR domains. This finding mirrors our previous observation of decreased IgG reactivity to VAR2CSA in a different set of samples from the Ghana study [20]. The lower breadth and intensity of IgG reactivity to Pf EMP1-derived antigens affected all Pf EMP1 functional domain types in Ghana and Uganda; thus, the reduced IgG reactivity is unrelated to Pf EMP1 functional phenotype.…”

Capture and Detection of Circulating Glioma Cells Using the Recombinant VAR2CSA Malaria Protein

“…When considering previously published data showing that ofCS is presented by nearly all cancer cells of epithelial, mesenchymal, and hematopoietic origin, the use of rVAR2 staining reagent for CTC detection would be beneficial over traditional single-surface markers [25,27,33,34]. Here, we show that captured glioma CTCs can be identified by an rVAR2 stain.…”

“…We have previously shown that the rVAR2 protein interacts with ofCS present on cancer cell lines representing almost all known cancers [25,33,34]. We tested rVAR2 binding to a panel of cell lines, including low-grade (WHO grade II) diffuse glioma (Res259) as well as high-grade (WHO grade IV) GBM (U87mg, KNS-42, and U118mg), to test for the presence of ofCS in glioma.…”

Inverse association of falciparum positivity with endemic Burkitt lymphoma is robust in analyses adjusting for pre-enrollment malaria in the EMBLEM case-control study

“…Children with immunity to malaria have a lower risk of death from severe malaria [ 16 , 18 ], but they are exposed to chronic falciparum parasitemia and increased activity by splenic macrophages to clear parasites [ 17 ]. We suggest that this increased falciparum antigenic load to the spleen is a risk factor for eBL [ 45 ] in children in malaria endemic regions. We further infer that it is not high-risk falciparum variants (as is the case for severe malaria), but the multiplicity of diverse variants the children are exposed to that are the risk factor for eBL [ 46 ].…”