Studies on Monoclonal Gammopathies

描述（由申请人提供）：多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，从临床良性前体疾病发展而来，包括癌前状态未确定意义的单克隆伽玛病（MGUS）和无症状期称为阴燃型MM （SMM）。从MGUS到SMM和明显的、成熟的MM的进展是非常多变的。为什么有些患者病情进展，而另一些患者一生都没有发生MM，这仍然是一个重要的临床问题。这个高度整合的项目的总体目标是阐明MGUS -> - SMM -> - MM ->复发性MM的进展原因，以了解如何最好地临床处理疾病的每个阶段。在项目1中，Rajkumar博士建议确定进展的预测因素，允许定义一个具有足够高进展风险的MGUS患者子集，以保证干预；他还将研究遗传或家族因素在MGUS中的作用以及阴燃骨髓瘤的流行病学。在项目2中，Jelinek博士假设单克隆伽玛病的标志性特征——克隆内异质性包括肿瘤细胞生长潜力的异质性。假设的增殖亚群存在于疾病所有阶段的单克隆（由免疫球蛋白序列定义）PC池中，即MGUS -> SMM -> MM ->复发性MM，该细胞群可能利用正常造血干细胞和/或早期B细胞祖细胞所采用的一些机制。因此，她将研究MGUS/SMM浆细胞和疾病进展过程中的克隆内异质性。她还将分离和表征增殖细胞，并研究与MGUS/SMM/MM细胞中正常干细胞的肿瘤发生和生长控制相关的两种特定途径的作用。在项目3中，Fonseca博士将确定IgH易位是否在某些PC肿瘤的发病机制中是重要事件，如果是，它们的转录后果是什么。他还将使用分子细胞遗传学来阐明MGUS和MM的致病途径，以及MGUS/MM患者是否具有获得IgH易位的潜在易感性。核心A将集中数据和样本收集和处理，为每个项目提供适当的材料。核心B将在项目设计中发挥关键作用，并将提供个别项目数据的统计分析。核心C将提供一个行政结构，以加强互动并支持定期的内部和外部科学审查。本项目的主要具体目标继续是更好地了解单克隆伽玛病的病理生理学。我们相信这些结果最终将转化为改进和新颖的治疗策略。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable malignancy of plasma cells that evolves from clinically benign precursor conditions, including the premalignant condition monoclonal gammopathy of undetermined significance (MGUS) and an asymptomatic stage called smoldering MM (SMM). The progression from MGUS to SMM and overt, full-blown MM is quite variable. The reason(s) why some patients progress whereas others live out their lives without ever developing MM remains an important clinical question. The overall goal of this highly integrated program is to elucidate the causes of progression from MGUS -> SMM -> MM -> relapsed MM to learn how best to clinically approach each stage of the disease. In Project 1, Dr. Rajkumar proposes to identify predictors of progression permitting definition of a subset of MGUS patients with a risk of progression high enough to warrant intervention; and the premalignant stage responsible for light chain-only MM. He will also examine the role of genetic or familial factors in MGUS and the epidemiology of smoldering myeloma. In Project 2, Dr. Jelinek hypothesizes that intraclonal heterogeneity, a hallmark feature of the monoclonal gammopathies, includes heterogeneity in tumor cell growth potential. The hypothesized proliferative subset is suggested to exist within the monoclonal (as defined by immunoglobulin sequence) PC pool at all phases of disease, i.e., MGUS -> SMM -> MM -> relapsed MM, and this population of cells may utilize some mechanisms employed by normal hematopoietic stem cells and/or early B cell progenitors. She will therefore study intraclonal heterogeneity in MGUS/SMM plasma cells and during disease progression. She will also isolate and characterize proliferating cells and study the role of two specific pathways linked to oncogenesis and growth control of normal stem cells in MGUS/SMM/MM cells. In Project 3, Dr. Fonseca will determine if IgH translocations are seminal events in the pathogenesis of some PC neoplasms and if so, what are their transcriptional consequences. He will also use molecular cytogenetics to elucidate pathogenic pathways in both MGUS and MM and whether MGUS/MM patients have an underlying susceptibility to acquire IgH translocations. Core A will centralize data and sample collection and processing providing appropriate materials for each project. Core B will play a key role in project design and will provide statistical analysis of individual project data. Core C will provide an administrative structure to enhance interaction and support regular internal and external scientific review. The major Specific Aim of this Program Project continues to be obtaining a better understanding of the pathophysiology of the monoclonal gammopathies. We believe that these results will ultimately translate into improved and novel therapeutic strategies.