The Role of Exosome Heparanase and miRNAs as Biomarkers for Myeloma

描述(申请人提供)：多发性骨髓瘤(MM)是一种浆细胞恶性肿瘤，其特征是细胞对凋亡产生抵抗，导致肿瘤细胞在骨髓微环境中长期存活和积聚。多发性骨髓瘤的标准化发病率正在增加，在非裔美国人和男性中通常高出两倍。虽然MM的病因尚不清楚，但它之前的先兆无症状性浆细胞营养不良被称为未确定意义的单克隆性伽马病(MGUS)和阴燃骨髓瘤(SMM)。尽管已经有了临床风险模型、基因组异常和成像，但利用这些指标准确地对早期先兆疾病进行分类和监测临床病程的努力尚未成功。或者，最近在转录组测序方面的进展为将miRNAs表征为新的生物标记物提供了新的机会，这可能显著改变MM的分类、管理和治疗的范式。拟议的探索性/发展性调查的目标是表征强大的肿瘤调节因子乙酰肝素酶(HPSE)和外体MircroRNAs(MiRNA)作为生物标志物的作用，以早期发现、分类和进展从无症状前体状态发展为多发性骨髓瘤的高风险个体。我们将检验最重要的假设，即血清外切体、HPSE和miRNA图谱与骨髓瘤进展相关。为了解决这一假设，我们打算：(1)表征从MGUS、SMM和MM患者以及性别、年龄、血统匹配的对照组的血清中分离的外切体中的HPSE蛋白水平；(2)在血清外切体中进行miRNA谱分析；以及(3)确定HPSE影响外切体miRNA组成与骨髓瘤进展相关的程度。我们打算利用一个独特的机会，在一个庞大的、特征良好的骨髓瘤人群中探索这些关系，同时利用HPSE和外切体生物学以及基因组测序方面的最新进展。我们预计，这项研究的结果将是非常有用的，并为提出骨髓增多症的生物学机制以及新的疾病生物标记物提供必要的基础。这些新的生物标志物可以显著改变骨髓瘤的诊断、分类、管理和治疗模式，并通过降低与晚期疾病相关的发病率和死亡率来提高总体存活率。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a plasma cell malignancy characterized by cellular resistance to apoptosis leading to prolonged survival and accumulation of tumor cells in the bone marrow microenvironment. Standardized incidence rates of MM are increasing and are typically two-fold higher among African Americans and men. Although the etiology of MM is unclear, it is preceded by precursor asymptomatic plasma cell dyscrasias known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Despite the availability of clinical risk models, genomic aberrations and imaging, efforts to utilize these indices to accurately classify early stage precursor disease and monitor clinical course have not been successful. Alternatively, recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of MM classification, management and treatment. The goal of the proposed Exploratory/Developmental investigation is to characterize the role of heparanase (HPSE), a potent tumor regulator, and exosome mircroRNAs (miRNA) as biomarkers for early detection, classification and progression of individuals at highest risk for developing MM from asymptomatic precursor states. We will test the overarching hypothesis that serum exosome HPSE and miRNA profiles correlate with myeloma progression. To address this hypothesis we intend to: (1) characterize HPSE protein levels in exosomes isolated from the sera of patients with MGUS, SMM and MM and sex-, age-, ancestry-matched controls; (2) conduct miRNA profiling in serum exosomes; and (3) determine the extent to which HPSE influences exosome miRNA composition relative to myeloma progression. We intend to capitalize on a unique opportunity to explore these relationships in a large, well-characterized population of myeloma, while taking advantage of recent advances in HPSE and exosome biology and genome sequencing. We anticipate that findings from this investigation will be highly informative and provide the foundation necessary to propose biologic mechanisms underlying myelomagenesis as well as new biomarkers for disease. These novel biomarkers could significantly change the paradigm for myeloma diagnosis, classification, management and treatment and improve overall survival by reducing morbidity and mortality associated with advanced stage disease.