PO.TB04.04 · 肿瘤生物学
缺失必需即刻早期反式激活因子RTA/ORF50的KSHV基因组在转基因小鼠中诱导血管肉瘤
The KSHV genome, devoid of the essential immediate early transactivator RTAORF50, induces angiosarcoma in transgenic mice
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摘要 Abstract
中文摘要
卡波西肉瘤相关疱疹病毒（KSHV）广泛改变宿主细胞信号，诱导多种恶性和癌前表型，包括卡波西肉瘤（KS）。由于缺乏动物模型，KSHV最初诱导KS的机制仍不明确，因为人类病原体KSHV不能有效感染啮齿类动物或非人灵长类。我们实验室近期通过将完整的160-kb KSHV病毒基因组整合到小鼠种系中，从而绕过啮齿类对病毒复制的屏障，建立了KS的小动物模型。KSHV转基因小鼠发生的鼠源血管肉瘤在组织学和转录谱上与人类KS无法区分；然而，需要删除病毒miRNA基因座，转基因创始动物才能产生后代。由此产生了FVBNJ-Tg(HHV8)197DtmrMmnc品系（Cell Host Microbe. 2024 32(5):755-767）。我们现已生成另一种KSHV转基因小鼠品系，其携带全部病毒miRNA，但缺失即刻早期反式激活因子RTA/ORF50，后者对诱导裂解基因转录既是必要的也是充分的。在缺失RTA/ORF50的情况下，病毒miRNA与胚胎发育相容。完整的转基因以孟德尔方式传递，纯合子动物存活。Tg(HHV8dRta)小鼠的总生存期显著更高，但仍会发生血管肉瘤。RTA对鼠源KS可有可无这一发现，对病毒复制在KSHV致癌中的作用具有重要意义。在进一步研究之前，我们假设RTA依赖性基因并非肿瘤形成所必需。或者，在其他疱疹病毒中被归类为严格裂解性的转录本，在KSHV中可能具有其他调控方式。源自HHV8dRta鼠源KS肿瘤的肿瘤细胞系可在培养中无限增殖，为KSHV研究提供了一种强有力的新工具。我们将展示携带或不携带该必需即刻早期反式激活因子的KSHV转基因小鼠肿瘤生物学的详细比较。
查看英文原文 English abstract
Kaposi Sarcoma-associated herpesvirus (KSHV) extensively alters host cell signaling to induce a variety of malignant and premalignant phenotypes, including Kaposi sarcoma (KS). The mechanisms by which KSHV initially induces KS remain unclear due to a lack of animal models, as the human pathogen KSHV does not productively infect rodents or non-human primates. Our lab has recently developed a small-animal model of KS by integrating the entire 160-kb KSHV viral genome into the germline of mice, thereby circumventing rodent barriers to viral replication. KSHV transgenic mice develop a murine angiosarcoma indistinguishable from human KS by histology and transcriptional profile; however, deletion of the viral miRNA locus was required for the transgene founder animals to produce offspring. This yielded the FVBNJ-Tg(HHV8)197DtmrMmnc line (Cell Host Microbe. 2024 32(5):755-767). We have now generated another KSHV transgenic mouse line that carries all viral miRNAs but lacks the immediate-early transactivator RTA/ORF50, which is necessary and sufficient to induce lytic gene transcription. Without RTA/ORF50, the viral miRNAs are compatible with embryonic development. The intact transgene is transmitted in Mendelian fashion, and homozygous animals are viable. The Tg(HHV8dRta) mice have significantly higher overall survival but still develop angiosarcoma. The dispensability of RTA for murine KS has significant implications for the role of viral replication in KSHV oncogenesis. Pending further studies, we hypothesize that RTA-dependent genes are not required for tumor formation. Alternatively, transcripts that are classified as strictly lytic in other herpesviruses may have alternative modes of regulation in KSHV. Tumor cell lines derived from HHV8dRta murine KS tumors grow indefinitely in culture, providing a powerful new tool for KSHV research. A detailed comparison of tumor biology in KSHV transgenic mice with or without the essential immediate early transactivator will be presented.
利益披露 Disclosure
D. P. Dittmer, None..
K. Shifflett, None..
E. B. Anthony, None..
S. Huanjuan, None..
Z. Zhang, None..
B. Damania, None.