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1.
Eur J Immunol ; 52(8): 1273-1284, 2022 08.
Article En | MEDLINE | ID: mdl-35503749

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.


APOBEC Deaminases , Burkitt Lymphoma , Cytidine Deaminase , Epstein-Barr Virus Infections , Malaria, Falciparum , APOBEC Deaminases/genetics , APOBEC-3G Deaminase , Burkitt Lymphoma/enzymology , Burkitt Lymphoma/genetics , Cytidine Deaminase/genetics , Epstein-Barr Virus Infections/enzymology , Epstein-Barr Virus Infections/genetics , HEK293 Cells , Herpesvirus 4, Human , Humans , Malaria, Falciparum/enzymology , Malaria, Falciparum/genetics , Minor Histocompatibility Antigens , Mutagens
2.
Cancer Immunol Immunother ; 71(6): 1371-1392, 2022 Jun.
Article En | MEDLINE | ID: mdl-34668039

Endemic Burkitt lymphoma (eBL) is an aggressive B cell cancer characterized by an IgH/c-myc translocation and the harboring of Epstein-Barr virus (EBV). Evidence accumulates that CD4 + T cells might contribute to eBL pathogenesis. Here, we investigate the presence of CD4 + T cells in primary eBL tissue and their potential dichotomous impact on an EBV-infected pre-eBL cell model using ex vivo material and in vitro co-cultures. In addition, we establish a novel method to study the effect of IgH/c-myc translocation in primary B cells by employing a CRISPR/Cas9 knock-in approach to introduce and tag de novo translocation. We unprecedently document that CD4 + T cells are present in primary eBL tumor tissue. Furthermore, we demonstrate that CD4 + T cells on the one hand suppress eBL development by killing pre-eBL cells lacking IgH/c-myc translocation in vitro and on the other hand indirectly promote eBL development by inducing crucial EBV Latency III to Latency I switching in pre-eBL cells. Finally, we show that while the mere presence of an IgH/c-myc translocation does not suffice to escape CD4 + T-cell-mediated killing in vitro, the CD4 + T-cell-mediated suppression of EBV's Latency III program in vivo may allow cells harboring an IgH/c-myc translocation and additional mutations to evade immune control and proliferate by means of deregulated c-myc activity, resulting in neoplasia. Thus, our study highlights the dichotomous effects of CD4 + T cells and the mechanisms involved in eBL pathogenesis, suggests mechanisms of their impact on eBL progression, and provides a novel in vitro model for further investigation of IgH/c-myc translocation.


Burkitt Lymphoma , Epstein-Barr Virus Infections , B-Lymphocytes/metabolism , Burkitt Lymphoma/genetics , Cell Survival , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/genetics , Herpesvirus 4, Human , Humans
3.
Cancer Immunol Immunother ; 70(8): 2275-2289, 2021 Aug.
Article En | MEDLINE | ID: mdl-33507341

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. The two-step BCP-ALL pathogenesis requires in utero-induced chromosomal aberrations and additional mutagenic events for overt leukemia. In mouse models, activation-induced cytidine deaminase (AID/AICDA) was suggested to contribute to BCP-ALL pathogenesis by off-target mutagenic activity. The role of AID in patients, however, remains unclear. Moreover, AID is usually not expressed in precursor B-cells but in germinal center B-cells, where it is induced upon T-helper (Th) cell stimulation. We have previously demonstrated that autologous Th-cells supportively interacted with BCP-ALL-cells. Here, we hypothesize that this interaction additionally induces AID expression in BCP-ALL-cells, leading to off-target mutagenic activity. We show that co-culture with autologous bone marrow Th-cells induced high AICDA expression in primary BCP-ALL-cells. This induction was mediated by a mechanism similar to the induction in mature B-cells involving IL-13/Stat6, CD40L/NF-κB and TGFß/Smad2/3 signaling. Even though Th-cell-induced AID seemed to be active in vitro in a BCP-ALL reporter cell line, extensive mutational signature analysis revealed no major contribution of AID activity to the mutational landscape in BCP-ALL patients. AID activity was neither detected in mutation clusters nor in known AID targets. Moreover, no recurrently mutated gene showed a relevant enrichment of mutations in the AID motif. Together, the lack of AID-induced mutational consequences argues towards a Th-cell-promoted yet AID-independent BCP-ALL pathogenesis and favors therapeutic research focusing on Th-cell-derived support of BCP-ALL-cells rather than AID-induced effects.


Bone Marrow/immunology , Cytidine Deaminase/immunology , Lymphoma, B-Cell/immunology , Mutagenesis/immunology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adolescent , Adult , B-Lymphocytes/immunology , Cell Line, Tumor , Cells, Cultured , Child , Child, Preschool , Female , Humans , Infant , Male , Mutation/immunology , Signal Transduction/immunology , Young Adult
4.
Oncogene ; 38(13): 2420-2431, 2019 03.
Article En | MEDLINE | ID: mdl-30532071

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.


B-Lymphocytes/immunology , Bone Marrow/immunology , Cell Proliferation/physiology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , T-Lymphocytes, Helper-Inducer/immunology , Th1 Cells/immunology , ADP-ribosyl Cyclase 1/metabolism , B-Lymphocytes/metabolism , Bone Marrow/metabolism , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Humans , Interferon-gamma/metabolism , Phenotype , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , T-Lymphocytes, Helper-Inducer/metabolism , Th1 Cells/metabolism , Up-Regulation/immunology
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