Molecular Pathogenesis of Multiple Myeloma

多发性骨髓瘤的分子发病机制

• 批准号: 8061624
• 负责人: Peter Leif Bergsagel
• 金额: $ 32.2万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061624
• 关键词: 11q13; 4p16; 6p21; American; American Cancer Society; Animal Model; Bortezomib; CCND1 gene; Cell Line; Chromosomal translocation; Chromosomes, Human, Pair 3; Cyclin D1; DNA; Development; Dexamethasone; Diagnosis; Disease; Disease Progression; Drug effect disorder; Drug resistance; Event; FGFR3 gene; Future; Gene Expression; Gene Mutation; Genetic; Genetic Models; Genomics; Health; Immunoglobulin Genes; Immunoglobulins; Individual; Intervention; Laboratories; Lead; Malignant Neoplasms; Molecular; Multiple Myeloma; Mus; Mutation; NF-kappa B; Other Genetics; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Recurrence; Relapse; Relative (related person); Role; Sampling; TNF receptor-associated factor 3; Thalidomide; Therapeutic; Time; Transgenic Mice; Trisomy; base; c-myc Genes; cancer diagnosis; clinically significant; design; drug development; lenalidomide; mouse model; novel; response; tumor; tumor progression

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.

描述（由申请人提供）：2007 年，美国癌症协会估计将有 19,900 人被诊断出患有多发性骨髓瘤 (MM)，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。该项目将利用遗传学方法探索骨髓瘤疾病发生、进展、药物反应和耐药性的分子基础。既往研究表明，MM有两种主要的遗传亚型，一种以反复发生免疫球蛋白基因易位为特征，涉及5个位点（4p16 FGFR3/MMSET、16q23 c-maf、20q11 mafB、11q13 CCND1、6p21 CCND3）；另一种是多发性骨髓瘤（MM）。另一种缺乏这些易位，其特征是超二倍体，具有 3、5、7、9、11、15、19 和 21 号染色体的多重三体性。两种 MM 亚型共有的次要遗传事件包括 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 拷贝水平变化进行综合基因组分析，我们发现了一系列杂乱的突变，这些突变在约 20% 的 MM 患者（主要是那些没有超二倍体的患者）中激活非典型 NFkB 通路。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在功能上验证 MM 中非典型 NFkB 通路激活的后果。最后，我们将采取直接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，我们将分析疾病进展前后采集的患者的配对样本。总而言之，我们预计这些研究结果将为个体化治疗、现有药物的合理组合和测序提供基础，并为未来药物开发工作确定目标。