Myc-activating chromosomal translocations

我们继续我们的研究染色体易位，解除调控Myc原癌基因在B细胞后，并列的调节序列的免疫球蛋白（IG）重链或轻链基因。Myc激活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： (i)我们发现，携带突变Myc基因的小鼠自发发生B细胞淋巴瘤，其组织学、细胞学、表型和分子特征类似于人BL，所述突变Myc基因由重建的IG轻链基因座（l或k）控制，所述轻链基因座含有建立体外基因座控制所需的所有元件。我们将这些肿瘤命名为小鼠伯基特淋巴瘤。 (ii)我们已经证明，BALB/c浆细胞瘤典型的12;15易位可以通过将Myc插入到IG重链位点来模拟。Myc在Cm上游的插入重建了浆细胞瘤宿主典型的Cm/Myc重组，而Myc在Ca的5'端的插入再现了在成熟浆细胞瘤中最常见的Myc交换类型（Ca/Myc重组）。我们证明了基因靶向的Cm/Myc小鼠和Ca/Myc小鼠易于发生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)我们已经表明，可移植的浆细胞瘤窝藏Myc激活12;15易位自发发展的未经处理（无降植烷）BALB/c小鼠的淋巴组织下的组织相容性H2-Ld启动子的转录控制下的人IL-6转基因。这一发现表明，三个致病因素的合作是至关重要的小鼠PCT的发展：组成性IL-6信号（IL 6的转基因表达），激活Myc（12;15易位），和PCT易感等位基因（BALB/c基因型）。

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).