Molecular Pathogenesis of Multiple Myeloma

项目摘要 2007年，美国癌症协会估计，将有19,900人被诊断出患有癌症，10,790人将死亡。 多发性骨髓瘤（MM）最近对患者治疗的改进是经验性的， MM患者对硼替佐米、沙利度胺和来那度胺特别敏感的分子基础是 不清楚该项目将使用遗传学方法来探索骨髓瘤疾病发生的分子基础， 进展、药物反应和耐药性。以前的研究表明，有两个主要的遗传因素， MM的亚型，一种以涉及5个基因座（4p 16）的复发性免疫球蛋白基因易位为特征 FGFR 3/MMSET、16 q23 c-maf、20 q11 mafB、11 q13 CCND 1、6p 21 CCND 3）;以及其他缺乏这些的 易位，并且特征在于超二倍体，具有染色体3，5，7，9，11，15， 19和21两种MM亚型共有的次级遗传事件包括ras的激活突变， p53失活突变和myc易位。最近，通过一项综合基因组分析， 基因表达和DNA拷贝水平的变化，我们发现了一种混杂的 在约20%的MM患者中激活非经典NFkB通路的一系列突变，主要是那些 没有超二倍体。此外，我们发现NFkB通路组成性激活的患者似乎 对硼替佐米治疗特别敏感我们将探讨这些突变的临床意义 在疾病进展、药物反应和耐药性方面。我们将在功能上验证 使用细胞系和动物模型在MM中非经典NFkB途径活化的后果。 最后，我们将采取定向的方法来鉴定与疾病相关的新的遗传事件 进展为了实现这一点，我们将分析在治疗前后从患者中采集的配对样本。 疾病进展的发展。总之，我们预计这些研究的结果将提供 个体化治疗的基础，以及现有药物的合理组合和排序，并将确定 未来药物开发的目标。

Project Summary In 2007, the American Cancer Society estimates that 19,900 will be diagnosed with, and that 10,790 will die from multiple myeloma (MM). Recent improvements in the treatment of patients have been empiric, and the molecular basis for the particular sensitivity of MM patients to bortezomib, thalidomide and lenalidomide is unclear. This project will use a genetic approach to explore the molecular basis of myeloma disease initiation, progression, drug response and drug resistance. Previous studies have shown that there are two main genetic subtypes of MM, one characterized by recurrent immunoglobulin gene translocations involving five loci (4p16 FGFR3/MMSET, 16q23 c-maf, 20q11 mafB, 11q13 CCND1, 6p21 CCND3); and the other lacking these translocations, and characterized by hyperdiploidy, with multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. Secondary genetic events common to both MM subtypes include activating mutations of ras, inactivating mutations of p53, and translocations of myc. Recently, through an integrated genomic analysis of gene expression and DNA copy level changes in myeloma patients and cell lines, we identified a promiscuous array of mutations that activate the non canonical NFkB pathway in ~20% of MM patients, predominantly those without hyperdiploidy. Moreover, we found that patients with constitutive activation of the NFkB pathway seem to be particularly sensitive to bortezomib treatment. We will explore the clinical significance of these mutations in terms of disease progression, drug response and drug resistance. We will functionally validate the consequences of activation of the non-canonical NFkB pathway in MM using cell line and animal models. Finally, we will take a directed approach to the identification of novel genetic events associated with disease progression. To accomplish this, we will analyze paired samples from patients taken before and after the development of disease progression. Altogether, we anticipate that the results of these studies will provide the basis for individualized therapy, and rational combination and sequencing of existing drugs, and will identify the targets for future drug development efforts.