Myc-induced B cell and plasma cell neoplasms in mice

我们继续研究染色体易位导致原癌基因Myc在B细胞和浆细胞中表达失调。Myc激活的染色体易位是人类伯基特淋巴瘤（BL）和小鼠浆细胞瘤（PCT）的标志性突变。在过去的一个财政年度，我们在三个项目领域取得了重大进展： 我们已经证明，小鼠携带突变Myc基因控制的重建的IG轻链位点（l或k）含有所有元素，需要建立基因座控制在体外自发发展B细胞淋巴瘤的组织学，细胞学，表型和分子特征类似于人BL。我们将这些肿瘤命名为小鼠伯基特淋巴瘤。 我们已经表明，BALB/c小鼠携带的人IL-6转基因的转录控制下的组织相容性H2-Ld启动子自发发展浆细胞瘤。肿瘤发生在肠道相关淋巴组织，含有Myc激活T（12;15）易位，易于移植。我们的研究结果表明，以下三个致病因素的合作是至关重要的PCT在小鼠中的发展：组成性IL-6信号（IL-6的转基因表达），激活Myc（染色体易位），和PCT易感等位基因（BALB/c基因型）。 我们已经确定，Myc激活的T（12;15）易位在小鼠和相应的t（8;14）易位在人类中可以通过基因插入在小鼠中模仿。插入Myc的Cm上游重建的Cm-Myc重组，这是常见的人散发性伯基特淋巴瘤和小鼠浆细胞瘤的前体。Ca的Myc 5'的插入再现了在成熟小鼠浆细胞瘤中最常见的Myc交换类型。基因靶向小鼠易于发生肿瘤性B细胞和浆细胞发育，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谱系细胞中的肿瘤进展机制，并为Myc依赖性B细胞和浆细胞肿瘤设计新的预防和治疗方法。

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.