Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Animal Science, University of California Davis, Davis, CA 95616, USA.
Genes (Basel). 2021 Oct 17;12(10):1630. doi: 10.3390/genes12101630.
The avian α-herpesvirus known as Marek's disease virus (MDV) linearly integrates its genomic DNA into host telomeres during infection. The resulting disease, Marek's disease (MD), is characterized by virally-induced lymphomas with high mortality. The temporal dynamics of MDV-positive (MDV) transformed cells and expansion of MD lymphomas remain targets for further understanding. It also remains to be determined whether specific host chromosomal sites of MDV telomere integration confer an advantage to MDV-transformed cells during tumorigenesis. We applied MDV-specific fluorescence in situ hybridization (MDV FISH) to investigate virus-host cytogenomic interactions within and among a total of 37 gonad lymphomas and neoplastic splenic samples in birds infected with virulent MDV. We also determined single-cell, chromosome-specific MDV integration profiles within and among transformed tissue samples, including multiple samples from the same bird. Most mitotically-dividing cells within neoplastic samples had the cytogenomic phenotype of 'MDV telomere-integrated only', and tissue-specific, temporal changes in phenotype frequencies were detected. Transformed cell populations composing gonad lymphomas exhibited significantly lower diversity, in terms of heterogeneity of MDV integration profiles, at the latest stages of tumorigenesis (>50 days post-infection (dpi)). We further report high interindividual and lower intraindividual variation in MDV integration profiles of lymphoma cells. There was no evidence of integration hotspots into a specific host chromosome(s). Collectively, our data suggests that very few transformed MDV T cell populations present earlier in MDV-induced lymphomas (32-50 dpi), survive, and expand to become the dominant clonal population in more advanced MD lymphomas (51-62 dpi) and establish metastatic lymphomas.
已知禽类α疱疹病毒马立克氏病病毒（MDV）在感染过程中会将其基因组 DNA 线性整合到宿主端粒中。由此引发的疾病，即马立克氏病（MD），以病毒诱导的淋巴瘤和高死亡率为特征。MDV 阳性（MDV）转化细胞的时间动态和 MD 淋巴瘤的扩展仍然是进一步理解的目标。仍然需要确定 MDV 端粒整合到特定的宿主染色体位置是否在肿瘤发生过程中赋予 MDV 转化细胞优势。我们应用 MDV 特异性荧光原位杂交（MDV FISH）来研究感染强毒 MDV 的鸟类总共 37 个性腺淋巴瘤和肿瘤性脾样本中的病毒-宿主细胞遗传学相互作用。我们还确定了单个细胞、染色体特异性的 MDV 整合谱，包括来自同一鸟类的多个样本。在肿瘤样本中的大多数有丝分裂分裂细胞具有“仅 MDV 端粒整合”的细胞遗传学表型，并且检测到表型频率的组织特异性、时间变化。在肿瘤发生的晚期（>50 天感染后（dpi）），组成性腺淋巴瘤的转化细胞群体表现出明显更低的多样性，即 MDV 整合谱的异质性。我们进一步报告了淋巴瘤细胞中 MDV 整合谱的个体间变异性高，个体内变异性低。没有证据表明整合热点进入特定的宿主染色体。总的来说，我们的数据表明，在 MDV 诱导的淋巴瘤早期（32-50 dpi）存在的极少数转化 MDV T 细胞群体存活下来，并扩展成为更晚期 MD 淋巴瘤（51-62 dpi）中的主要克隆群体，并建立转移性淋巴瘤。
