c-IMycI-induced B cell and plasma cell neoplasms in mice

我们继续研究小鼠B细胞和浆细胞肿瘤的发病机制，这些肿瘤是由染色体T（12;15）易位引起的，导致原癌基因Myc（c-myc）的表达失调。小鼠T（12; BALB/c浆细胞瘤（PCT）的标志性突变是人类MYC激活t（8;14）（q24;q32）易位的直接对应物，该易位最常见于人类伯基特淋巴瘤（BL）。在过去的一个财政年度，我们在以下项目领域取得了重大进展： 在转基因小鼠中使用基因插入，我们成功地模拟了人BL t（8;14）（q24;q32）/小鼠PCT T（12;15）易位的三种不同状态。新开发的菌株被命名为“iMyc”。“我们最近的研究表明，iMyc-Em小鼠容易患肿瘤性B细胞和浆细胞肿瘤，包括淋巴母细胞B细胞淋巴瘤（LBL）、弥漫性大B细胞淋巴瘤（DLBCL）和浆细胞瘤（PCT）。这些一起是成熟B细胞的肿瘤，其与人类B细胞衍生的非霍奇金淋巴瘤非常相关（Cancer Res.65：1306-1315，2005）。几条证据表明，iMyc-Em小鼠为设计和测试用于治疗和预防人B细胞和浆细胞肿瘤的新方法提供了良好的机会。 由于MYC和BCL-XL的表达失调是人浆细胞肿瘤多发性骨髓瘤（MM）的一致特征，我们研究了Myc和Bcl-XL在小鼠浆细胞中的靶向表达是否可能导致人MM的改善小鼠模型。我们将我们新开发的iMyc菌株之一iMyc-Ca与含有由小鼠Igk 3'增强子驱动的BCL-XL转基因的小鼠杂交。单转基因BCL-XL小鼠在380天龄时保持无肿瘤，单转基因Myc小鼠很少发生B细胞肿瘤（9.3%）。然而，双转基因Myc/BCL-XL小鼠发生浆细胞肿瘤，发病时间短（平均135天），肿瘤发生率为100%。肿瘤浸润骨髓，在某些情况下导致溶骨性病变。这些发现表明，通过在浆细胞中具有峰值活性的增强子强制表达Myc和BCL-XL在小鼠中产生肿瘤，其概括了人MM的关键特征（J.Clin.Invest. 113：1763-1773，2004）。 在相关的细胞遗传学工作中，我们研究了染色体超结构对小鼠B系细胞中Myc激活染色体易位起源的可能作用。我们研究了Myc，Igh和Igk在正常或罗伯逊融合染色体上的位置是否会影响小鼠Myc易位和浆细胞瘤（PCT）的发展，但发现情况并非如此。然而，在Rb（6.15）小鼠中，染色体倒位与染色体易位竞争Igk-Myc并置，前者比后者更常见。这第一次表明，间期核中Igk和Myc的空间接近性促进了这些基因座的非法遗传重排（Genes Chromosomes Cancer 42：416-426，2005）。我们的研究结果表明，Myc易位依赖的小鼠PCTs提供了一个很好的模型系统，以促进我们对高阶基因组组织，染色体易位起源和癌症发展之间关系的理解。 我们已经进一步证明，Myc依赖性腹膜PCT在小鼠中，炎症依赖性浆细胞转化的首要实验模型，是有用的阐明癌症预防的机制。在一项关于微量营养素硒的研究中，我们发现缺硒小鼠对PCT完全无效。

We have continued our studies on the pathogenesis of mouse B cell and plasma cell neoplasms that are induced by chromosomal T(12;15) translocations that result in the deregulated expression of the proto-oncogene Myc (c-myc). The mouse T(12;15) translocation, the hallmark mutation of BALB/c plasmacytoma (PCT), is the direct counterpart of the human MYC-activating t(8;14)(q24;q32) translocation that is most commonly seen in human Burkitt lymphoma (BL). In the past fiscal year we have made significant advances in the following project areas: Using gene insertion in transgenic mice, we have successfully mimicked three different states of the human BL t(8;14)(q24;q32)/mouse PCT T(12;15) translocation. The newly developed strains were designated "iMyc." Our most recent work has shown that the iMyc-Em mice are prone to neoplastic B cell and plasma cell neoplasms, including lymphoblastic B-cell lymphoma (LBL), diffuse large B cell lymphoma (DLBCL) and plasmacytoma (PCT). Together these are tumors of mature B cells, which are of great relevance for B-cell derived non-Hodgkin's lymphomas in humans (Cancer Res. 65:1306-1315, 2005). Several lines of evidence indicate that the iMyc-Em mouse affords a good opportunity to design and test new approaches for the treatment and prevention of human B cell and plasma cell tumors. Because deregulated expression of MYC and BCL-XL are consistent features of the human plasma cell neoplasm, multiple myeloma (MM), we have investigated whether targeted expression of Myc and Bcl-XL in mouse plasma cells might lead to an improved mouse model of human MM. We crossed one of our newly developed iMyc strains, iMyc-Ca, with mice that contain a BCL-XL transgene driven by the mouse Igk 3' enhancer. Single transgenic BCL-XL mice remained tumor free by 380 days of age and single transgenic Myc mice developed B-cell tumors infrequently (9.3%). However, double transgenic Myc/BCL-XL mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). The tumors infiltrated the bone marrow and caused, in some cases, osteolytic lesions. These findings demonstrated that the enforced expression of Myc and BCL-XL by enhancers with peak activity in plasma cells generates tumors in mice that recapitulate key features of human MM (J. Clin. Invest. 113:1763-1773, 2004). In related cytogenetic work, we have studied the possible role of chromosome suprastructure on the origin of Myc-activating chromosomal translocations in mouse B-lineage cells. We investigated whether the location of Myc, Igh, and Igk on normal or Robertsonian fusion chromosomes affects Myc translocations and plasmacytoma (PCT) development in mice, but found that this was not the case. However, in Rb(6.15) mice, in which chromosomal inversions competed with chromosomal translocations for Igk-Myc juxtapositions, the former were found more frequently than the latter. This indicated, for the first time, that the spatial proximity of Igk and Myc in the interphase nucleus facilitates the illegitimate genetic rearrangement of these loci (Genes Chromosomes Cancer 42:416-426, 2005). Our findings suggest that Myc translocation-dependent mouse PCTs provide a good model system to advance our understanding of the relationship of higher-order genome organization, origin of chromosomal translocations, and development of cancer. We have further demonstrated that Myc-dependent peritoneal PCT in mice, the premier experimental model of inflammation-dependent plasma cell transformation, is useful to elucidate mechanisms of cancer prevention. In a study on the micronutrient selenium, we showed that selenium-depleted mice were totally refractory to PCT.