MECHANISMS OF CELL MYELOMA CELL GROWTH CONTROL

多发性骨髓瘤(MM)是一种以恶性浆细胞聚集为特征的常见致命性疾病 (PC)在骨髓中。因此，至关重要的是要确定在从 癌前状态，即未确定意义的单克隆性伽马病(MGUS)，到更具侵袭性 疾病状态，例如MM。MM细胞的生长特征，以及MGUS中较小程度的PC 患者，与正常终末期PC形成鲜明对比。尽管有这种重要的表型差异 在MM/MGUS细胞和正常PC之间，MM的总体增殖指数很低。无能为力 目前根除这种疾病的治疗策略助长了这样一种观念，即在 对针对更多分化的肿瘤细胞的药物具有相对抵抗力的骨髓瘤细胞库 或者没有进一步的增长潜力。考虑到相当大的表型、形态和遗传异质性 在肿瘤细胞中观察到，我们假设存在广泛更新的MM细胞亚群 在这种疾病中，存在于克隆PC池中的能力。同样，这个隔间也很可能 在MGUS中存在，并了解克隆进化和该细胞生长调节的差异 MM与MGUS的间隔区是了解疾病进展的关键。我们进一步假设 MM和MGUS患者的这一克隆PC子集的生长控制机制 重叠，至少部分与造血干细胞和/或早期B细胞前体细胞利用的机制重叠 具有内在的自我更新能力。越来越多的证据表明，在正常情况下 具有自我更新能力的细胞和癌细胞，包括转化相关基因表达的重新激活 转录因子通常只在正常的早期B系发育过程中活跃。因为我们的 初步数据和最新文献将Wnt/Frizzleed/13-catenin/Lef-1和Polycomb Group基因联系在一起， Bmi-1和EZH2，对早期造血细胞的自我更新和肿瘤的发生，我们已经假设基因在 这两条通路在这种疾病中被不适当地激活，特别是在肿瘤细胞亚群中。 具有自我更新的特性。为了解决这些假设，我们提出了四个具体目标：1)分析PC MGUS患者的克隆内同质性或异质性(由Ig、VDJ或VJ序列定义) 未进展为骨髓瘤；2)评估MM和MGUS细胞亚群的生长潜力；3)表征 非增殖期MM/MGUS细胞与MM/MGUS细胞的遗传学和表型差异 具有自我更新能力；以及4)具体研究Wnt/Frizzleed/13-catenin/Lef-1途径的作用和 聚梳组基因Bmi-1和EZH2与MM 9生长控制

Multiple myeloma (MM) is a universally fatal disease characterized by the accumulation of malignant plasma cells (PC) in the bone marrow. It is, therefore, crucial to identify the changes that occur during the progression from preneoplastic states, i.e., monoclonal gammopathy of undetermined significance (MGUS), to more aggressive disease states, e.g., MM. The growth characteristics of MM cells, and to a lesser extent PCs from MGUS patients, are in striking contrast with those of normal end-stage PCs. Despite this important phenotypic difference between MM/MGUS cells and normal PCs, the overall proliferative index of MM is quite low. The inability of current therapeutic strategies to eradicate this disease has fueled the notion that there is a subpopulation within the myeloma cell pool that is relatively resistant to agents that target more differentiated tumor cells with little or no further growth potential. Given the considerable phenotypic, morphologic, and genetic heterogeneity observed among tumor cells, we hypothesize there is a subpopulation of MM cells with extensive renewal capability that exists within the monoclonal PC pool in this disease. Similarly, this compartment is also likely to exist in MGUS and understanding clonal evolution and the differences in growth regulation of this cellular compartment in MM vs. MGUS is key to understanding disease progression. We further hypothesize that the mechanisms of growth control in this subset of monoclonal PCs from MM and perhaps MGUS patients will overlap, at least in part with mechanisms utilized by hematopoietic stem cells and/or early B cell progenitors that possess intrinsic self-renewal capabilities. There is growing evidence of the striking parallels between normal cells with self-renewal capability and cancer cells, including transformation-related reactivation of expression of transcription factors that are typically active only during normal early B lineage development. Because of our preliminary data and recent literature linking the Wnt/frizzled/13-catenin/LEF-1 and the Polycomb Group genes, Bmi-1 and EZH2, to early hematopoietic cell self-renewal and oncogenesis, we have hypothesized that genes in these two pathways have been inappropriately activated in this disease, particularly in the subset of tumor cells that has self-renewal properties. To address these hypotheses, we propose four specific aims: 1) analyze PC intraclonal homogeneity or heterogeneity (as defined by Ig VDJ or VJ sequence) in MGUS patients that do or do not progress to myeloma; 2) assess the growth potential of MM and MGUS cell subpopulations; 3) characterize the genetic and phenotypic differences that exist between non-proliferating MM/MGUS cells and MM/MGUS cells with self-renewal capability; and 4) specifically study the role of the Wnt/frizzled/13-catenin/LEF-1 pathway and the Polycomb Group genes Bmi-1 and EZH2 in MM 9rowth control.