Epstein-Barr virus and malaria upregulate AID and APOBEC3 enzymes, but only AID seems to play a major mutagenic role in Burkitt lymphoma.
Epstein-Barr virus and malaria upregulate AID and APOBEC3 enzymes, but only AID seems to play a major mutagenic role in Burkitt lymphoma.
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DOI：
10.1002/eji.202249820
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发表时间：
2022-08
影响因子：
5.4
通讯作者：
Bürgler S
中科院分区：
文献类型：
--
作者：
Summerauer AM;Jäggi V;Ogwang R;Traxel S;Colombo L;Amundsen E;Eyer T;Subramanian B;Fehr J;Mantel PY;Idro R;Bürgler S
地方性伯基特淋巴瘤 (eBL) 的特点是致癌的 IGH/c-MYC 易位和 Epstein-Barr 病毒 (EBV) 阳性，并且在流行病学上与恶性疟原虫疟疾有关。人们认为 EBV 和疟疾都通过诱导激活诱导的胞苷脱氨酶 (AID) 的表达来促进 eBL，AID 是一种参与 IGH/c-MYC 易位的酶。 AID/载脂蛋白 B mRNA 编辑催化多肽样 (AID/APOBEC) 家族酶最近已成为多种癌症中有效的诱变来源，但除了 AID 之外，它们在 eBL 中的参与以及 EBV 和恶性疟原虫的调节尚不清楚。在这里，我们发现，接种 EBV 后，人类 B 细胞强烈上调具有酶活性的 APOBEC3B 和 APOBEC3G 的表达。此外，我们发现疟疾患者 B 细胞中 APOBEC3A 水平显着升高，这与寄生虫负载相关。有趣的是，尽管 APOBEC3A、APOBEC3B 和 APOBEC3G 在 HEK293T 细胞中过表达时会引起 c-MYC 突变，但 eBL 肿瘤中的突变富集仅在 AID 基序中检测到。这表明，尽管 EBV 和恶性疟原虫定向的免疫反应触发了几种 AID/APOBEC 成员的表达和活性，但只有 AID 的上调才具有致癌后果，而 APOBEC3 亚家族的诱导可能主要具有免疫保护功能。图解摘要：Epstein-Barr 病毒和恶性疟原虫疟疾上调人类 B 细胞中激活诱导的胞苷脱氨酶 (AID) 和几种 APOBEC3 酶，但只有 AID 衍生的驱动基因突变在伯基特淋巴瘤肿瘤中富集。这表明伯基特淋巴瘤的致癌突变主要是由 AID 引起的，而 APOBEC3 酶主要具有免疫保护功能。
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. Graphical Abstract: Epstein–Barr virus and Plasmodium falciparum malaria upregulate activation‐induced cytidine deaminase (AID) and several APOBEC3 enzymes in human B cells, but only AID‐derived driver‐gene mutations are enriched in Burkitt lymphoma tumors. This suggests that oncogenic mutations in Burkitt lymphoma are predominantly caused by AID, while APOBEC3 enzymes have primarily immunoprotective functions.
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影响因子：
64.5
作者：
Robbiani DF;Bothmer A;Callen E;Reina-San-Martin B;Dorsett Y;Difilippantonio S;Bolland DJ;Chen HT;Corcoran AE;Nussenzweig A;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
64.5
作者：
Robbiani DF;Deroubaix S;Feldhahn N;Oliveira TY;Callen E;Wang Q;Jankovic M;Silva IT;Rommel PC;Bosque D;Eisenreich T;Nussenzweig A;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
6.4
作者：
Bobrovnitchaia, Irina;Valieris, Renan;da Silva, Israel T.
通讯作者：
da Silva, Israel T.
影响因子：
5.2
作者：
Moris A;Murray S;Cardinaud S
通讯作者：
Cardinaud S
影响因子：
64.5
作者：
Ramiro, AR;Jankovic, M;Nussenzweig, MC
通讯作者：
Nussenzweig, MC