Molecular Pathogenesis of Multiple Myeloma

描述（由申请人提供）：2007年，美国癌症协会估计将有19,900人被诊断患有多发性骨髓瘤，10,790人将死于多发性骨髓瘤（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尚不清楚。本项目将采用遗传学方法探索骨髓瘤发病、进展、药物反应和耐药性的分子基础。先前的研究表明，MM有两种主要的遗传亚型，一种以复发性免疫球蛋白基因易位为特征，涉及五个位点（4p16 FGFR3/MMSET, 16q23 c-maf, 20q11 mafB, 11q13 CCND1, 6p21 CCND3）；而另一种则缺乏这些易位，其特征是高二倍体，具有多个染色体3、5、7、9、11、15、19和21的三体。两种MM亚型共有的继发性遗传事件包括ras激活突变、p53失活突变和myc易位。最近，通过对骨髓瘤患者和细胞系的基因表达和DNA拷贝水平变化的综合基因组分析，我们在约20%的骨髓瘤患者（主要是那些没有高二倍体的患者）中发现了一组混杂的突变，这些突变激活了非规范的NFkB途径。此外，我们发现NFkB通路构成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在疾病进展、药物反应和耐药性方面的临床意义。我们将使用细胞系和动物模型从功能上验证非规范NFkB通路在MM中激活的后果。最后，我们将采取一种直接的方法来识别与疾病进展相关的新遗传事件。为了实现这一目标，我们将分析患者在疾病进展之前和之后的成对样本。总之，我们期望这些研究结果将为个体化治疗、现有药物的合理组合和排序提供基础，并为未来药物开发工作确定靶点。公共卫生相关性：多发性骨髓瘤是一种致命的癌症，每年有2万美国人被诊断出来。该建议旨在了解导致这种疾病形成和最终进展的特定分子原因。这将有助于我们设计出更有效、毒性更小的疗法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Multiple myeloma is a deadly cancer diagnosed in 20,000 Americans annually. This proposal seeks to understand the specific molecular causes that lead to the formation, and ultimate progression of this disease. This will help us to design more active and less toxic therapies.