MOLECULAR CYTOGENETICS OF MULTIPLE MYELOMA

多发性骨髓瘤（MM）是一种致命的肿瘤疾病，其起源、进展和临床行为的遗传机制尚不清楚。提出的研究是基于这样的假设，即利用当前可用的尖端技术对MM进行详细的遗传表征，将使人们对这一重要的造血恶性肿瘤的生物学和临床行为有新的认识。在这些研究中，我们建议将光谱核型（SKY）和比较基因组杂交（CGH）这两种新的分子细胞遗传学技术与染色体易位失调基因的克隆和表征技术相结合。本应用程序有三个具体目的：我们将应用分子细胞遗传学技术SKY和CGH对一系列前瞻性确定的MM肿瘤样本进行诊断评估，并进入纪念医院（MH）治疗方案，以充分表征该疾病各个阶段的结构重排（SKY）和数值异常（CGH）。2. 通过与IG基因重排分离出解除调控的新基因。我们将从新的14q32 （IGH）相关染色体易位中分离和表征候选脱调控基因。我们在这些肿瘤的首次SKY研究中发现的两个易位t(12;14)（q24;q32）和t(14;20)（q32;q11）将作为克隆的初始目标。3. 开发MM的新遗传预后模型。我们将开发MM的遗传预后模型，利用SKY和CGH的数据，对进入纪念医院治疗方案的患者进行反复重排、断点、染色体区域的获得和损失，以及传统的预后标志物，如β -微球蛋白、血清IL-2-6和c反应蛋白的水平。CGH确定的分区域得失也可以确定基因的扩增或失活可能影响临床结果的位点。我们对MM的初步研究以及我们之前在b细胞非霍奇金淋巴瘤（NHL）分析中取得的类似成功，使我们有信心在本申请中提出的研究中取得成功。

Multiple myeloma (MM) is a fatal neoplastic disease whose genetic mechanisms of origin, progression, and clinical behavior are poorly understood. The proposed studies are based on the hypothesis that detailed genetic characterization of MM utilizing currently-available cutting-edge technologies will enable a new understanding of the biology and clinical behavior of this important hematopoietic malignancy. In these studies, we propose to combine the two novel molecular cytogenetic techniques, spectral karyotyping (SKY) and comparative genomic hybridization (CGH), with those of cloning and characterization of genes deregulated in chromosomal translocations. This applicatin has three Specific Aims: 1. Define chromosomal changes in MM using CGH and SKY We will apply the molecular cytogenetic techniques SKY and CGH to a series of prospectively ascertained MM tumor samples seen for diagnostic evaluation and entered on Memorial Hospital (MH treatment protocols in order to fully characterize structural rearrangements (SKY) and numerical abnormalities (CGH) at all stages of the disease. 2. Isolate novel genes deregulated by rearrangement with IG genes. We will isolate and characterize the candidate deregulated genes from novel 14q32 (IGH)-associated chromosomal translocations. The two translocations, t(12;14)(q24;q32) and t(14;20)(q32;q11), discovered in the first SKY study of these tumors by us will be initially targeted for cloning. 3. Develop a new genetic prognostic model for MM. We will develop a genetic prognostic model for MM utilizing data from SKY and CGH on recurring rearrangements, breakpoints, and gains and losses of chromosomal regions, along with conventional prognostic markers such as levels of beta2-microglobulin, serum IL-2-6, and C-reactive protein, on patients entered on Memorial Hospital treatment protocols. The subregional gains and losses identified by CGH may also identify sites of genes whose amplification or inactivation may influence clinical outcome. Our preliminary studies of MM and our previous success with similar goals in the analysis of B-cell non-Hodgkin's lymnphoma (NHL), give us the confidence that we will be successful in the studies proposed in this application.