MOLECULAR CYTOGENETIC OF DIFFUSE LARGE CELL LYMPHOMA

在这份申请中，我们建议继续我们正在进行的研究，目的是 在分子发病机制和临床行为方面的认识 DLLC是非霍奇金淋巴瘤(NHL)的一个临床重要亚型。这个 拟议的研究有两个目标。其中一个目标是对一种新的 一种称为异位易位的染色体畸变型。 染色体位置的混杂重排参与复发 涉及IgH基因和其他染色体位置的易位 这表明这些位点的候选基因可能被解除了调控。 通过形成嵌合基因产物或通过利用 不相关的推动者。将实现以下试验性目标： (1)分离和鉴定候选的去调控基因 混杂排列染色体1q21、12p12、12q24和15q13 通过与免疫球蛋白基因相关的重排。(2)。从分子上讲 描述染色体位置上的重排 参与非14q32关联的易位子集，涉及 错配易位位点3q27/BCL6。所针对的染色体位置 因为此分析将折衷为：1q21、2q21、4p11和5q13。品种繁多 克隆策略，包括基于免疫球蛋白基因重排的策略， 融合基因5‘端新基因的定位克隆及鉴定 RACE技术中已知重排基因的信使核糖核酸将被利用。 这些研究的基础假设是对正常和 参与这种易位的基因功能的解除将 有助于了解DLLC的生物学特性。第二个目标是 这个应用是为了开发一个基于DLLC的遗传预后模型 影响非调控基因的重排，特异的扩增 基因，以及由基因决定的染色体区域的拷贝数变化 比较基因组杂交技术。这些基因 终点将与已建立的临床预后标记物相关 例如细胞类型以及体积和疾病程度的测量。一个 将进行回顾分析和前瞻性分析，后者 基于进入MSKCC淋巴瘤方案的患者，NHL15M。这个 这些研究背后的假设是，临床的遗传基础 结果是复杂的，不仅取决于放松对特定领域的监管 基因，也对基因和染色体区域的拷贝数变化有影响。 概述的研究将检验所提出的假设；它们是 这是我们之前对DLLC研究的合乎逻辑的扩展，可以预期 使我们更好地了解猪的生物学和临床行为 这种病。

In this application, we propose to continue our on-going studies aimed at understanding the molecular pathogenesis and clinical behavior of DLLC, a clinically important subset of non-Hodgkin's lymphoma (NHL). The proposed studies have two aims. One aim is molecular analysis of a new class of chromosome aberration called promiscuous translocation. Promiscuously rearranging chromosomal sites participate in recurring translocations involving the IGH gene as well as other chromosomal sites suggesting that the candidate genes at these sites may be deregulated either by formation of chimeric gene products or by utilization of unrelated promoters. The following experimental goals will be pursued: (1) To isolate and characterize the candidate deregulated genes at the promiscuously rearranging chromosomal sites 1q21, 12p12, 12q24, and 15q13 through IGH-gene-associated rearrangements. (2). To molecularly characterize the rearrangements at the chromosomal sites which participate in non-14q32-associated translocation subsets involving the promiscuous translocation site 3q27/BCL6. The chromosomal sites targeted for this analysis will compromise: 1q21, 2q21, 4p11, and 5q13. A variety of cloning strategies including those based on IGH gene rearrangement, positional cloning, and identification of novel mRNA species fused 5' of mRNA of known rearranged genes by the RACE technique, will be utilized. The hypothesis underlying these studies is that analysis of normal and deregulated function of genes involved in such translocations will contribute to an understanding of the biology of DLLC. A second aim of this application is to develop a genetic prognostic model for DLLC based on rearrangements affecting deregulated genes, amplification of specific genes, and copy number changes of chromosomal regions determined by the comparative genomic hybridization (CGH) technique. These genetic endpoints will be correlated with established clinical prognostic markers such as cell type and measures of bulk and extent of disease. A retrospective and a prospective analysis will be undertaken, the latter based on patients entered on the MSKCC Lymphoma protocol, NHL15M. The hypothesis underlying these studies is that the genetic basis of clinical outcome is complex and depends not only on deregulation of specific genes, but also on copy number changes of genes and chromosomal regions. The studies outlined will test the hypotheses proposed; they are a logical extension of our previous studies of DLLC and can be expected to lead to a better understanding of the biology and clinical behavior of this disease.