ANTIGEN RECEPTORS AND THE BIOLOGY OF DIFFUSE AGGRESSIVE LYMPHOMA

这个项目是基于我们实验室最近的发现 弥漫性侵袭性淋巴瘤有显著的使用 免疫球蛋白VH4.21基因为其抗原结合受体。我们有 在一系列有限的未经选择的患者中发现，18名患者中有11名 这些肿瘤表达的免疫球蛋白重链来源于 VH4.21基因。这些VH基因大多由肿瘤细胞表达 包含相对于其生殖系对应的突变，并且几乎 所有这些突变都发生在克隆扩增之前 肿瘤。这一发现与我们之前在毛囊中的发现形成了鲜明对比。 淋巴瘤，其中对任何特定的V区基因没有偏见 注意到，并且在克隆扩展期间发生正在进行的体细胞突变 滤泡性淋巴瘤肿瘤。因此滤泡性淋巴瘤和弥漫性淋巴瘤 大细胞淋巴瘤是生物学上不同的疾病。鉴于 滤泡性淋巴瘤似乎是在正常的B细胞内随机发展的 细胞群，弥漫性大细胞淋巴瘤似乎起源于 直接命中表达特定VH基因的一组受限细胞。 此外，尽管滤泡性淋巴瘤经常产生核酸 作为肿瘤克隆的其表达的免疫球蛋白基因的突变 在持续刺激的影响下扩大可能 抗原，弥漫性大细胞淋巴瘤肿瘤不改变其 随着肿瘤的扩大，免疫球蛋白基因。 第二个具有挑衅性的发现是免疫球蛋白使用 VH4.21基因对人具有结合活性和杀伤活性 B细胞。这一发现引出了许多关于脑血管紧张素转换酶作用的假说。 VH4.21基因在弥漫性大细胞淋巴瘤发病中的作用 在本项目中，我们将：1.确定vh4.21基因的真实流行率。 弥漫性侵袭性B细胞淋巴瘤的表达，2.确定是否 VH4.21的表达与卵巢癌临床或生物学参数的相关性 肿瘤的确切组织学类型、临床转归和活动性 肿瘤内的其他基因，如bcl6、myc或bcl23。确定 肿瘤产生的蛋白质产物是否与特定的 自身抗原，特别是B淋巴细胞上的抗原，4.决定 这些由肿瘤产生的蛋白质对B细胞具有杀伤活性 淋巴细胞和这种杀伤活性是否延伸到肿瘤细胞 它们产生了这些蛋白质。这些发现应该会带来更好的 对弥漫侵袭性B细胞淋巴瘤发病机制的认识 可提供构建诊断探针的方法和 治疗这种疾病的治疗策略。

This project is based on the recent finding from our laboratory that diffuse aggressive lymphomas have a striking propensity to use the immunoglobulin VH4.21 gene for their antigen binding receptor. We have found, in a limited series of unselected patients, that 11 out of 18 of these tumors express an immunoglobulin heavy chain that was derived from the VH4.21 gene. Most of these VH genes expressed by the tumor cells contain mutations with respect to their germ line counterparts, and almost all of these mutations had occurred prior to the clonal expansion of th tumor. This finding contrasts with our previous findings in follicular lymphomas, where no bias toward any particular V region gene has been noted, and where ongoing somatic mutation occurs during clonal expansion of the follicular lymphoma tumors. Thus follicular lymphomas and diffuse large cell lymphomas are biologically distinct diseases. Whereas follicular lymphoma appears to develop as a random hit within the normal B cell population, diffuse large cell lymphoma appears to arise from a directed hit on a restricted set of cells expressing particular VH genes. Furthermore, whereas follicular lymphomas frequently generate nucleic acid mutations within their expressed immunoglobulin genes as the tumor clone expands possible under the influence of continuing stimulation by an antigen, diffuse large cell lymphoma tumors do not alter their immunoglobulin genes as the tumor expands. A second provocative finding has been that immunoglobulin proteins using the VH4.21 gene can have a binding activity and a killing activity on human B cells. This finding leads to a number of hypotheses about the role of the VH4.21 gene in the pathogenesis of diffuse large cell lymphoma. In this project we will: 1. determine the true prevalence of VH4.21 gene expression in diffuse aggressive B cell lymphomas, 2. determine whether the expression of VH4.21 correlates with clinical or biological parameters of the tumors such as exact histologic type, clinical outcome and activation of other genes within the tumor such as bcl-6, myc or bcl-23. determine whether the protein products produced by the tumors bind to specific autoantigens, in particular antigens on B lymphocytes, 4. determine whether these proteins produced by the tumors have a killing activity on B lymphocytes and whether this killing activity extends to the tumor cells which have produced these proteins. These findings should lead to a better understanding of the pathogenesis of diffuse aggressive B cell lymphoma and may provide approaches to the construction of diagnostic probes and therapeutic strategies for the treatment of this disease.