Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapies.

Endemic Burkitt lymphoma (BL) is a childhood cancer in sub-Saharan Africa characterized by Epstein-Barr virus and malaria-associated aberrant B-cell activation and MYC chromosomal translocation. Survival rates hover at 50% after conventional chemotherapies; therefore, clinically relevant models are necessary to test additional therapies. Hence, we established five patient-derived BL tumor cell lines and corresponding NSG-BL avatar mouse models. Transcriptomics confirmed that our BL lines maintained fidelity from patient tumors to NSG-BL tumors. However, we found significant variation in tumor growth and survival among NSG-BL avatars and in Epstein-Barr virus protein expression patterns. We tested rituximab responsiveness and found one NSG-BL model exhibiting direct sensitivity, characterized by apoptotic gene expression counterbalanced by unfolded protein response and mTOR pro-survival pathways. In rituximab-unresponsive tumors, we observed an IFN-α signature confirmed by the expression of IRF7 and ISG15. Our results demonstrate significant inter-patient tumor variation and heterogeneity, and that contemporary patient-derived BL cell lines and NSG-BL avatars are feasible tools to guide new therapeutic strategies and improve outcomes for these children.

Plasmodium parasitophorous vacuole membrane-resident protein UIS4 manipulates host cell actin to avoid parasite elimination.

Parasite-derived PVM-resident proteins are critical for complete parasite development inside hepatocytes, although the function of most of these proteins remains unknown. Here, we show that the upregulated in infectious sporozoites 4 (UIS4) protein, resident at the PVM, interacts with the host cell actin. By suppressing filamentous actin formation, UIS4 avoids parasite elimination. Host cell actin dynamics increases around UIS4-deficient parasites, which is associated with subsequent parasite elimination. Notably, parasite elimination is impaired significantly by the inhibition of host myosin-II, possibly through relieving the compression generated by actomyosin complexes at the host-parasite interface. Together, these data reveal that UIS4 has a critical role in the evasion of host defensive mechanisms, enabling hence EEF survival and development.