Myc-induced B cell and plasma cell neoplasms in mice

我们继续对染色体易位进行研究，这些易位导致原癌基因Myc在B细胞和浆细胞中表达失控。MYC激活的染色体易位是人类Burkitt淋巴瘤(BL)和小鼠浆细胞瘤(PCT)的标志性突变。在上个财政年度，我们在三个项目领域取得了重大进展： 我们已经证明，携带突变的Myc基因的小鼠，由重建的Ig轻链基因座(L或k)控制，其中包含在体外建立基因座控制所需的所有元件，小鼠自发地发展为组织学、细胞学、表型和分子特征类似于人BL的B细胞淋巴瘤。我们已将这些肿瘤命名为小鼠Burkitt淋巴瘤。 我们已经证明，在组织相容性H2-LD启动子的转录控制下，携带人IL-6转基因的BALB/c小鼠自发地发生浆细胞瘤。肿瘤发生在肠道相关淋巴组织中，含有Myc激活的T(12；15)易位，很容易移植。我们的发现表明，以下三种致病因素的协同作用对小鼠PCT的发生发展至关重要：组成性IL-6信号(IL-6转基因表达)、Myc激活(染色体易位)和PCT易感等位基因(BALB/c基因)。 我们已经证实，通过在小鼠中插入基因，可以模拟小鼠中Myc激活的T(12；15)易位和人类中相应的t(8；14)易位。将Myc插入Cm的上游，重建了在人类散发性Burkitt淋巴瘤和小鼠浆细胞瘤的前体中常见的Cm-Myc重组。钙的Myc 5‘插入复制了在成熟的小鼠浆细胞瘤中最常见的Myc交换类型。基因靶向的小鼠容易发生肿瘤性B细胞和浆细胞发展，包括浆细胞瘤、滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤。这些小鼠目前被用于研究B系细胞中的肿瘤进展机制，并设计出依赖Myc的B细胞和浆细胞肿瘤的新预防和治疗方法。

We have continued our studies on chromosomal translocations that result in the deregulated expression of the proto-oncogene Myc in B cells and plasma cells. Myc-activating chromosomal translocations are the hallmark mutations of human Burkitt's lymphoma (BL) and mouse plasmacytoma (PCT). In the past fiscal year we have made significant advances in three project areas: We have demonstrated that mice bearing a mutated Myc gene controlled by reconstructed Ig light-chain loci (l or k) containing all elements required to establish locus control in vitro spontaneously develop B-cell lymphomas with histologic, cytologic, phenotypic, and molecular features resembling human BL. We have designated these tumors mouse Burkitt's lymphoma. We have shown that BALB/c mice harboring a human IL-6 transgene under the transcriptional control of the histocompatibility H2-Ld promoter spontaneously develop plasmacytomas. The tumors arise in gut-associated lymphoid tissues, contain Myc activating T(12;15) translocations, and are readily transplantable. Our finding suggests that the cooperation of the following three pathogenetic factors is crucial for PCT development in mice: constitutive IL-6 signaling (transgenic expression of IL-6), activation of Myc (chromosomal translocation), and PCT susceptibility alleles ( BALB/c genotype). We have established that the Myc-activating T(12;15) translocation in mice and the corresponding t(8;14) translocation in humans can be mimicked by gene insertion in mice. Insertion of Myc just upstream of Cm recreated the Cm-Myc recombination that is commonly found in human sporadic Burkitt's lymphoma and precursors of mouse plasmacytoma. Insertion of Myc 5' of Ca reproduced the type of Myc exchange that is most frequently observed in mature mouse plasmacytomas. The gene-targeted mice are prone to neoplastic B cell and plasma cell development, including plasmacytoma, follicular lymphoma, and diffuse large B cell lymphoma. The mice are currently used to study tumor progression mechanisms in B lineage cells and design new prevention and treatment approaches for Myc-dependent B cell and plasma cell tumors.