Myc-activating chromosomal translocations

在与免疫球蛋白(Ig)重链或轻链基因的调控序列并置后，我们继续了对B细胞中Myc原癌基因的染色体易位的研究。激活染色体易位的MYC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： (I)我们已经发现，含有Myc基因突变的小鼠，其所携带的Myc基因突变是由重建的Ig轻链基因座(L或k)控制的，该基因包含了在体外建立基因座控制所需的所有元件，小鼠自发地发展成具有类似于人BL的组织学、细胞学、表型和分子特征的B细胞淋巴瘤。我们已将这些肿瘤命名为小鼠Burkitt淋巴瘤。 (Ii)我们已经证明，通过将Myc插入Ig重链座位，可以模拟BALB/c浆细胞瘤-典型的12；15易位。插入Cm上游的Myc重建了浆细胞瘤前体典型的Cm/Myc重组，而插入Ca的Myc 5‘重现了成熟浆细胞瘤中最常见的Myc交换类型(Ca/Myc重组)。我们发现，基因靶向的Cm/Myc小鼠和Ca/Myc小鼠容易发生B细胞肿瘤，包括浆细胞瘤、滤泡性淋巴瘤和弥漫性大细胞淋巴瘤。这些肿瘤的生物学和分子特征是正在进行的研究的重点。 (Iii)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转基因的未处理(无Pristane)BALB/c小鼠的淋巴组织中自发发生了携带Myc激活的12；15易位的可移植浆细胞瘤。这一结果表明，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(12；15易位)和PCT易感等位基因(BALB/c基因)。

We have continued our studies on chromosomal translocations that deregulate the Myc proto-oncogene in B cells after juxtaposition to regulatory sequences of immunoglobulin (Ig) heavy- or light-chain genes. 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: (i) We have found 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. (ii) We have demonstrated that the BALB/c plasmacytoma-typical 12;15 translocation can be mimicked by inserting Myc into the Ig heavy-chain locus. Insertion of Myc upstream of Cm recreated the plasmacytoma precursor-typical Cm/Myc recombination, while insertion of Myc 5' of Ca reproduced the type of Myc exchange that is most frequently observed in mature plasmacytomas (Ca/Myc recombination). We demonstrated that gene-targeted Cm/Myc mice and Ca/Myc mice are prone to developing B-cell neoplasms, including plasmacytoma, follicular lymphoma, and diffuse large cell lymphoma. The biological and molecular characterization of these tumors is the focus of ongoing studies. (iii) We have shown that transplantable plasmacytomas harboring Myc activating 12;15 translocations develop spontaneously in lymphoid tissues of untreated (no pristane) BALB/c mice harboring a human IL-6 transgene under the transcriptional control of the histocompatibility H2-Ld promoter. This finding indicated that the cooperation of three pathogenetic factors is crucial for PCT development in mice: constitutive IL-6 signaling (transgenic expression of IL 6), activation of Myc (12;15 translocation), and PCT susceptibility alleles ( BALB/c genotype).