Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Blood Adv. 2022 Jul 26;6(14):4283-4296. doi: 10.1182/bloodadvances.2022007695.
MYC translocations in association with Epstein-Barr virus (EBV) infection are often observed in B-cell lymphomas. A subset of Burkitt lymphoma (BL) expresses EBV latent membrane proteins 1 and 2A (LMP1 and LMP2A) in addition to the typical restricted EBV latent gene expression. EBV-associated diffuse large B-cell lymphoma (DLBCL) typically exhibits latency type II or III and expresses LMP1. Here, we investigate the role of LMP1 in MYC-driven lymphomagenesis in our murine model. λ-MYC mice develop tumors having a "starry sky" appearance and have abnormal p53 expression that is also observed in human BL. LMP2A/λ-MYC double-transgenic mice develop tumors significantly faster than mice only expressing MYC. Similar to LMP2A/λ-MYC mice, LMP1/λ-MYC mice also have accelerated MYC-driven lymphomagenesis. As observed in LMP2A/λ-MYC mice, p27kip1 was degraded in LMP1/λ-MYC pretumor and tumor B cells. Coexpression of LMP1 and LMP2A resulted in the enhancement of B cell proliferation. In contrast to LMP2A, the inhibition of Syk or cyclin-dependant kinase (CDK)4/6 activity did not effectively inhibit LMP1-mediated MYC lymphomagenesis. Also, in contrast to LMP2A, LMP1 did not lessen abnormal p53 expression in λ-MYC tumors. To investigate the significance of LMP1 expression in human BL development, we reanalyzed RNA sequencing (RNA-Seq) data of primary human BL from previous studies. Interestingly, p53 mutations were less observed in LMP1-expressing BL, although they were not significantly changed by EBV infection, indicating LMP1 may lessen p53 mutations in human primary BL. This suggests that LMP1 effects in EBV-associated human BL vary from what we observe in our murine model. Finally, our studies suggest a novel pathogenic role of LMP1 in lymphomagenesis.
MYC 易位与 Epstein-Barr 病毒（EBV）感染常发生于 B 细胞淋巴瘤中。除了典型的 EBV 潜伏基因表达外，一部分 Burkitt 淋巴瘤（BL）还表达 EBV 潜伏膜蛋白 1 和 2A（LMP1 和 LMP2A）。EBV 相关弥漫性大 B 细胞淋巴瘤（DLBCL）通常表现为潜伏型 II 或 III，表达 LMP1。在此，我们在我们的小鼠模型中研究了 LMP1 在 MYC 驱动的淋巴瘤发生中的作用。λ-MYC 小鼠会发展出具有“星空”外观的肿瘤，并且存在异常的 p53 表达，这种表达也存在于人类 BL 中。LMP2A/λ-MYC 双转基因小鼠比仅表达 MYC 的小鼠发展肿瘤的速度快得多。与 LMP2A/λ-MYC 小鼠类似，LMP1/λ-MYC 小鼠也加速了 MYC 驱动的淋巴瘤发生。与 LMP2A/λ-MYC 小鼠一样，p27kip1 在 LMP1/λ-MYC 前肿瘤和肿瘤 B 细胞中被降解。LMP1 和 LMP2A 的共表达导致 B 细胞增殖增强。与 LMP2A 不同，抑制 Syk 或细胞周期依赖性激酶（CDK）4/6 活性并不能有效抑制 LMP1 介导的 MYC 淋巴瘤发生。此外，与 LMP2A 不同，LMP1 并不能减轻 λ-MYC 肿瘤中异常的 p53 表达。为了研究 LMP1 表达在人类 BL 发展中的意义，我们重新分析了之前研究中来自原发性人类 BL 的 RNA 测序（RNA-Seq）数据。有趣的是，尽管 EBV 感染没有显著改变，但在表达 LMP1 的 BL 中观察到的 p53 突变较少，表明 LMP1 可能减轻人类原发性 BL 中的 p53 突变。这表明 LMP1 在 EBV 相关人类 BL 中的作用与我们在小鼠模型中观察到的不同。最后，我们的研究表明 LMP1 在淋巴瘤发生中具有新的致病作用。
