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.

浆细胞增殖性疾病是 B 细胞的恶性肿瘤，全部表现为骨髓中的单克隆浆细胞。我们认为，多发性骨髓瘤 (MM) 的临床表现与意义未明的单克隆丙种球蛋白病 (MGUS) 的临床表现不同，因为在 MGUS 发展为 MM 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提供治疗策略，以防止转化为明显的 MM。我们之前工作的一个重要发现是对 MGUS 和 MM 患者血液中克隆相关 B 细胞进行分子鉴定。这些克隆相关的 B 细胞分化为成熟浆细胞的能力目前尚不清楚，而且该群体对于采用当前治疗策略的 MM 恶性转化和疾病复发的重要性也是未知的。我们的初步研究表明，这两种疾病之间存在的显着差异是，MM 患者的浆细胞比 MGUS 浆细胞表现出更高的生长速度和更低的凋亡率，并且 MM 的骨髓具有更高的微血管密度（血管生成）。这些差异可能是由于硫酸乙酰肝素蛋白聚糖（HSPG）的获得性过度表达造成的，例如结合成纤维细胞生长因子（FGF）的syndecan-1。目前尚不清楚这些与疾病相关的差异背后的机制，以及两种疾病中存在的克隆相关 B 细胞是否也具有这些趋势。该项目的目标是鉴定和表征克隆相关 B 细胞，确定其分化为成熟浆细胞的能力，分析浆细胞 HSPG、FGF 和 FGF 受体 (FGFR) 表达并了解 HSPG 的作用-FGF-FGFR信号复合物调节骨髓瘤细胞生长和凋亡。这项工作分为三个具体目标：(l) 鉴定 MGUS 或 MM 患者血液和骨髓中除浆细胞以外的克隆细胞，并表征其免疫学、分子和细胞遗传学特征； (2) 使用充分表征的体外激活系统确定患者血液中克隆相关 B 细胞的分化潜力； (3)研究骨髓瘤细胞系和MGUS或MM患者的单克隆浆细胞中FGF和FGFR表达的差异，并测定FGF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开发。