Burton Eric M, Liang Jin Hua, Mitra Bidisha, Asara John M, Gewurz Benjamin E
bioRxiv. 2024 Nov 8:2024.11.07.622457. doi: 10.1101/2024.11.07.622457.
Epstein-Barr virus (EBV) is associated with multiple types of cancers, many of which express the key viral oncoprotein Latent Membrane Protein 1 (LMP1). LMP1 is the only EBV-encoded protein whose expression is sufficient to transform both epithelial and B-cells. Although metabolism reprogramming is a cancer hallmark, much remains to be learned about how LMP1 alters lymphocyte oncometabolism. To gain insights into key B-cell metabolic pathways subverted by LMP1, we performed systematic metabolomic analyses on B cells with conditional LMP1 expression. This approach highlighted that LMP highly induces purine biosynthesis, with xanthosine-5-P (XMP) as one of the most highly LMP1-upregulated metabolites. Consequently, IMPDH inhibition by mycophenolic acid (MPA) triggered apoptosis of LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCL), a key model for EBV-driven immunoblastic lymphomas. Whereas MPA instead caused growth arrest of Burkitt lymphoma cells with the EBV latency I program, conditional LMP1 expression triggered their apoptosis. Although both IMPDH isozymes are expressed in LCLs, only IMPDH2 was critical for LCL survival, whereas both contributed to proliferation of Burkitt cells with the EBV latency I program. Both LMP1 C-terminal cytoplasmic tail domains critical for primary human B-cell transformation were important for XMP production, and each contributed to LMP1-driven Burkitt cell sensitivity to MPA. MPA also de-repressed EBV lytic antigens including LMP1 in latency I Burkitt cells, highlighting crosstalk between the purine biosynthesis pathway and the EBV epigenome. These results suggest novel oncometabolism-based therapeutic approaches to LMP1-driven lymphomas.
Altered metabolism is a hallmark of cancer, yet much remains to be learned about how EBV rewires host cell metabolism to support multiple malignancies. While the oncogene LMP1 is the only EBV-encoded gene that is sufficient to transform murine B-cells and rodent fibroblasts, knowledge has remained incomplete about how LMP1 alters host cell oncometabolism to aberrantly drive infected B-cell growth and survival. Likewise, it has remained unknown whether LMP1 expression creates metabolic vulnerabilities that can be targeted by small molecule approaches to trigger EBV-transformed B-cell programmed cell death. We therefore used metabolomic profiling to define how LMP1 signaling remodels the B-cell metabolome. We found that LMP1 upregulated purine nucleotide biosynthesis, likely to meet increased demand. Consequently, LMP1 expression sensitized Burkitt B-cells to growth arrest upon inosine monophosphate dehydrogenase blockade. Thus, while LMP1 itself may not be a therapeutic target, its signaling induces dependence on downstream druggable host cell nucleotide metabolism enzymes, suggesting rational therapeutic approaches.
爱泼斯坦 - 巴尔病毒（EBV）与多种类型的癌症相关，其中许多癌症表达关键的病毒癌蛋白潜伏膜蛋白1（LMP1）。LMP1是唯一一种其表达足以转化上皮细胞和B细胞的EBV编码蛋白。尽管代谢重编程是癌症的一个标志，但关于LMP1如何改变淋巴细胞肿瘤代谢仍有许多有待了解之处。为了深入了解被LMP1颠覆的关键B细胞代谢途径，我们对有条件表达LMP1的B细胞进行了系统的代谢组学分析。这种方法突出表明LMP1高度诱导嘌呤生物合成，5'-磷酸黄苷（XMP）是LMP1上调程度最高的代谢物之一。因此，霉酚酸（MPA）抑制肌苷单磷酸脱氢酶（IMPDH）会引发表达LMP1的EBV转化的淋巴母细胞系（LCL）凋亡，LCL是EBV驱动的免疫母细胞淋巴瘤的关键模型。而MPA反而导致具有EBV潜伏I程序的伯基特淋巴瘤细胞生长停滞，有条件的LMP1表达则引发其凋亡。尽管两种IMPDH同工酶都在LCL中表达，但只有IMPDH2对LCL存活至关重要，而两者都对具有EBV潜伏I程序的伯基特细胞增殖有贡献。对原代人B细胞转化至关重要的LMP1 C末端细胞质尾结构域对于XMP产生都很重要，并且各自促成LMP1驱动的伯基特细胞对MPA的敏感性。MPA还去抑制了潜伏I伯基特细胞中的包括LMP1在内的EBV裂解抗原，突出了嘌呤生物合成途径与EBV表观基因组之间的相互作用。这些结果提示了针对LMP1驱动的淋巴瘤的基于肿瘤代谢的新型治疗方法。
代谢改变是癌症的一个标志，但关于EBV如何重塑宿主细胞代谢以支持多种恶性肿瘤仍有许多有待了解之处。虽然癌基因LMP1是唯一一种足以转化小鼠B细胞和啮齿动物成纤维细胞的EBV编码基因，但关于LMP1如何改变宿主细胞肿瘤代谢以异常驱动受感染B细胞生长和存活的知识仍不完整。同样，LMP1表达是否会产生可被小分子方法靶向以触发EBV转化的B细胞程序性细胞死亡的代谢弱点也一直未知。因此，我们使用代谢组学分析来确定LMP1信号如何重塑B细胞代谢组。我们发现LMP1上调嘌呤核苷酸生物合成，可能是为了满足增加的需求。因此，LMP1表达使伯基特B细胞在肌苷单磷酸脱氢酶被阻断时对生长停滞敏感。因此，虽然LMP1本身可能不是一个治疗靶点，但其信号诱导对下游可药物化的宿主细胞核苷酸代谢酶的依赖性，提示了合理的治疗方法。
