文章：

IgM+淋巴增生性疾病的转基因小鼠模型，模拟华氏巨球蛋白血症

Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia

原文发布日期：2016-11-04

DOI: 10.1038/bcj.2016.95

类型: Original Article

开放获取: 是

英文摘要：

Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+ (IgM+) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, EμSV-BCL2-22 and H2-Ld-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2+IL6+AID− and found that they developed—with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)—a severe IgM+ lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2+IL6+AID− model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM.

摘要翻译： 

瓦尔登斯特伦巨球蛋白血症（WM）是一种低度恶性、无法治愈的免疫球蛋白M阳性（IgM+）淋巴浆细胞淋巴瘤，目前尚缺乏能够模拟肿瘤自发发展的基因工程小鼠模型。基于促炎细胞因子白介素6（IL6）和增强生存能力的癌蛋白B细胞白血病2（BCL2）在WM自然病程中起关键作用的证据，我们推测在无法进行免疫球蛋白类别转换重组的小鼠中强制表达IL6和BCL2，可能会诱发模拟WM的淋巴增殖性疾病。为验证这一假设，我们在激活诱导胞苷脱氨酶（AID）缺陷的遗传背景下，培育了携带人源BCL2（EμSV-BCL2-22）和IL6（H2-Ld-hIL6）转基因的复合转基因BALB/c小鼠。我们将这些BCL2+IL6+AID−小鼠命名为该模型，并发现它们以完全遗传外显率（100%发生率）和较短的潜伏期（中位生存期93天）发展出严重的IgM+淋巴增殖性疾病，重现了人类WM的重要特征。然而，该BCL2+IL6+AID−模型也存在缺陷，如血清IgM水平较低以及未在WM患者中观察到的组织病理学改变，这些结果表明需要对模型进行进一步优化，以实现与WM疾病特征更好的相关性。

原文链接：

Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia