CHARACTERIZATION AND GROWTH OF CLONALLY RELATED MYELOMA CELL

克隆相关骨髓瘤细胞的特征和生长

• 批准号: 6563836
• 负责人: Thomas E. Witzig
• 金额: $ 22.84万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-06 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563836
• 关键词: B lymphocyte; SCID mouse; apoptosis; bone marrow; cell differentiation; cell growth regulation; cell proliferation; clinical research; disease /disorder model; fibroblast growth factor; gammopathy; growth factor receptors; human subject; in situ hybridization; molecular oncology; multiple myeloma; neoplastic cell; neoplastic transformation; polymerase chain reaction; proteoglycan; receptor expression; tissue /cell culture

The plasma cell proliferative disorders are malignancies of B cells that all manifest as monoclonal plasma cells in the bone marrow. We believe that the clinical manifestations of multiple myeloma (MM) differ from those in monoclonal gammopathy of undetermined significance (MGUS) because of molecular and biological changes that occur in the clonal plasma cells during the progression from MGUS to MM. Since all MM cases likely originate as MGUS, understanding these biological differences could provide treatment strategies to prevent the transformation to overt MM. A key finding of our previous work has been the molecular identification of clonally related B cells in the blood of both MGUS and MM patients. The capacity of these clonally-related B cells to differentiate into mature plasma cells is currently unknown as is the significance of this population with respect to malignant transformation and disease relapse in MM following current treatment strategies. Our preliminary studies indicate that notable differences that exist between these two diseases are that plasma cells from MM patients exhibit higher growth and lower apoptotic rates than MGUS plasma cells and the marrow in MM has a higher microvessel density (angiogenesis). These differences may result from acquired overexpression of heparan sulfate proteoglycans (HSPG), such as syndecan- l, that bind fibroblast growth factors (FGFs). The mechanism(s) underlying these disease-relevant differences is currently unknown as is whether these trends are also shared by the clonally-related B cells present in both diseases. The goals of this project are to identify and characterize clonally-related B cells, determine their capacity to be differentiated to mature plasma cells, and to analyze plasma cell HSPG, FGF, and FGF receptor (FGFR) expression and learn the role of the HSPG-FGF-FGFR signaling complex in modulating myeloma cell growth and apoptosis. This work is organized into three specific aims: (l) to identify clonal cells other than plasma cells in the blood and marrow of patients with MGUS or MM and characterize their immunological, molecular, and cytogenetic features; (2) to determine the differentiation potential of clonally related B cells from the blood of patients using a well-characterized in vitro activation system; and (3) to investigate the differences in expression of FGFs and FGFRs in monoclonal plasma cells from myeloma cell lines and patients with MGUS or MM and to measure the effects of FGFs on myeloma cell proliferation and apoptosis. The results of these studies are certain to provide new insight into the key biological differences between MGUS and myeloma plasma cells as well as to guide the development of new treatment approaches that target all malignant cells.

浆细胞增生性疾病是一种B细胞的恶性肿瘤，在骨髓中都表现为单克隆性浆细胞。我们认为，多发性骨髓瘤(MM)的临床表现不同于意义不明的单克隆性伽马病(MGUS)，这是因为在从MGUS向MM进展的过程中，克隆性浆细胞发生了分子和生物学变化。由于所有MM病例都可能起源于MGUS，了解这些生物学差异可以为防止向显性MM转化提供治疗策略。我们先前工作的一个关键发现是对MGUS和MM患者血液中克隆性相关B细胞进行了分子鉴定。这些克隆性相关的B细胞分化为成熟浆细胞的能力目前尚不清楚，这一群体对于多发性骨髓瘤恶性转化和疾病复发的意义也是目前尚不清楚的。我们的初步研究表明，这两种疾病之间存在的显著差异是，MM患者的浆细胞比MGUS浆细胞表现出更高的生长和更低的凋亡率，并且MM患者的骨髓具有更高的微血管密度(血管生成)。这些差异可能是后天过表达的硫酸乙酰肝素蛋白多糖，如Syndecan-L，结合成纤维细胞生长因子(FGFs)。这些疾病相关差异背后的机制(S)目前尚不清楚，也不清楚这两种疾病中存在的克隆相关B细胞是否也具有这些趋势。本项目的目标是鉴定和鉴定克隆性相关的B细胞，确定其分化为成熟浆细胞的能力，分析浆细胞HSPG、FGFR和FGFR的表达，了解HSPG-FGFFR信号复合体在调节骨髓瘤细胞生长和凋亡中的作用。本工作分为三个特定目的：(1)鉴定MGUS和MM患者血液和骨髓中除浆细胞外的克隆性细胞并鉴定其免疫学、分子和细胞遗传学特征；(2)利用成熟的体外激活系统确定患者外周血中克隆相关B细胞的分化潜能；(3)研究骨髓瘤细胞系和MGUS或MM患者单克隆浆细胞中FGFs和FGFRs的表达差异，并检测FGFs对骨髓瘤细胞增殖和凋亡的影响。这些研究的结果肯定会为MGUS和骨髓瘤浆细胞之间的关键生物学差异提供新的见解，并指导针对所有恶性细胞的新治疗方法的发展。