Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis
Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis
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DOI：
10.1073/pnas.1401215111
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发表时间：
2014-05
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影响因子：
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通讯作者：
Ioanna Triviai;M. Ziegler;U. Bergholz;Andrew J. Oler;T. Stübig;V. Prassolov;B. Fehse;C. Kozak;N. Kröger;C. Stocking
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作者：
Ioanna Triviai;M. Ziegler;U. Bergholz;Andrew J. Oler;T. Stübig;V. Prassolov;B. Fehse;C. Kozak;N. Kröger;C. Stocking
意义免疫缺陷小鼠是定义驱动恶性肿瘤(癌症)的干细胞的重要工具。原发性骨髓纤维化(PMF)是一种慢性骨髓增生性肿瘤，可进展为恶性白血病。在一项在移植小鼠中确定PMF干细胞的研究中，我们观察到小鼠白血病的高发病率。我们发现，内源性逆转录病毒(ERV)在免疫缺陷小鼠中的复制不受限制，在PMF异种移植的微环境中是致病的，可能是因为PMF来源的细胞刺激了大量增殖的小鼠细胞。增殖细胞是逆转录病毒转化和自发突变的目标，因此容易诱发白血病。这些结果证实了旁分泌机制在PMF疾病中的重要性，并揭示了在通常用于模拟人类疾病的小鼠中复制ERV的存在。非肥胖糖尿病(NOD)近交系小鼠Prkdcsord和Il2rgnull等位基因纯合(NSG小鼠)的复合免疫缺陷允许广泛的原代人类细胞植入，从而能够对人类疾病进行复杂的建模。在旨在定义原发性骨髓纤维化(PMF)的肿瘤干细胞的研究中，我们观察到NSG小鼠发生急性髓系白血病(AML)的频率很高。PMF是一种骨髓增生性肿瘤，其特征是造血微环境严重破坏。AML起源于小鼠，仅限于PMF-异种移植小鼠，并含有多种生态嗜性小鼠白血病病毒(E-MuLV)的克隆性整合。值得注意的是，不仅在患病的小鼠中观察到了MuLV的复制，而且在未治疗的NSG对照组中也观察到了MuLV的复制。此外，除了位于NOD基因组中11号染色体(Emv30)上的单一生态嗜性内源性逆转录病毒(EERV)外，从四个独立的NSG小鼠群体中的每个小鼠身上都观察到了多个新生生殖系eERV整合。分析证实，E-MuLV起源于Emv30前病毒，重组事件不是病毒复制或AML诱导所必需的。因此，致病性可能归因于PMF介导的小鼠髓系细胞的旁分泌刺激，这些髓系细胞是逆转录病毒感染和转化的靶点，整合到Evi1基因位点就证明了这一点，Evi1基因是逆转录病毒诱导的髓系白血病的热点。因此，这项研究证实了旁分泌刺激在PMF疾病进展中的作用，强调了靶细胞类型和数量在MuLV诱导的疾病中的重要性，并要求在NOD免疫缺陷小鼠中意识到复制MuLV，这可能会显著影响实验结果及其解释。
Significance Immunodeficient mice are important tools to define stem cells that drive malignancies (cancers). Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm that can progress to malignant leukemia. In a study to define PMF stem cells in transplanted mice, we observed a high incidence of mouse leukemia. We show that endogenous retrovirus (ERV), whose replication is unrestricted in immunodeficient mice, are pathogenic in the PMF-xenograft microenvironment, likely because of increased numbers of proliferating mouse cells stimulated by PMF-derived cells. Proliferating cells are targets of retroviral transformation and spontaneous mutations, and thus susceptible to leukemia induction. These results substantiate the importance of paracrine mechanisms in PMF disease and expose the presence of replicating ERVs in mice commonly used to model human diseases. The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdcscid and Il2rgnull alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation.