MOLECULAR CYTOGENETIC OF DIFFUSE LARGE CELL LYMPHOMA

在这项申请中，我们建议继续我们正在进行的研究， 在了解分子发病机制和临床行为， DLLC，非霍奇金淋巴瘤（NHL）的临床重要亚类。的 拟议的研究有两个目的。一个目标是对一种新的 一种叫做混杂易位的染色体畸变。 杂乱重排的染色体位点参与了 涉及IGH基因以及其他染色体位点的易位 这表明这些位点的候选基因可能是去调控的， 或者通过形成嵌合基因产物，或者通过利用 无关的推动者。将努力实现以下实验目标： (1)为了分离和表征候选的去调控基因， 杂乱重排染色体位点1 q21、12 p12、12 q24和15 q13 通过IGH基因相关的重排。（二）、从分子上 表征染色体位点的重排， 参与非14 q32相关的易位亚群， 混杂易位位点3q 27/BCL 6。所针对的染色体位点 因为这种分析将涉及：1 q21、2 q21、4p 11和5 q13。 各种 包括IGH基因重排在内的克隆策略， 位置克隆和鉴定新的mRNA种类， 将利用通过RACE技术已知重排基因的mRNA。 这些研究背后的假设是，分析正常和 参与这种易位的基因的失调功能将 有助于了解DLLC的生物学。 的第二目的 本申请旨在开发DLLC的遗传预测模型， 影响失调基因的重排，特异性 基因，和染色体区域的拷贝数变化， 比较基因组杂交（CGH）技术。这些遗传 终点将与已建立的临床预后标志物相关 例如细胞类型和体积测量以及疾病程度。 一 将进行回顾性和前瞻性分析，后者 基于MSKCC淋巴瘤方案NHL 15 M的患者。的 这些研究背后的假设是，临床的遗传基础， 结果是复杂的，不仅取决于放松管制的具体 基因，但也对基因和染色体区域的拷贝数变化。 概述的研究将测试提出的假设;它们是一个 我们以前的DLLC研究的逻辑延伸，可以预期， 从而更好地了解生物学和临床行为， 这种疾病。

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.