P-5: Molecular markers of plasma cell neoplasm evolution

在这项拨款申请中，我们希望继续寻找导致和预测进展的标记 从MGUS到骨髓瘤(MM)。我们之前建立了一个参考队列患者，我们在这些患者中 载玻片和样品进行原位单细胞分析。自从我们上次提交拨款以来，我们已经 开发了基于寡核苷酸的阵列比较基因组杂交的专业知识并发表了 (ACGH)。我们提出以下建议，旨在更好地了解MGUS进展为MM和MM的原因 为了能够更好地预测，以便对患者进行更合适的咨询。最终这就是 信息将被用于开发新的治疗方法。在具体目标1中，我们希望挖掘 关于多发性骨髓瘤的现有基因组数据(包括解剖和功能)，并探索一些 新发现的标记物确实是进展事件。我们将从这些中减去那些已经存在的 MGUS。我们将测试它们作为预测标记，研究MGUS幻灯片，并搜索与 现有的基线细胞遗传学类别。在《特定目标2》中，我们将探讨myc是司机的可能性。 通过全面的基因组方法进展到MM的事件，包括全基因组，高 密度，平铺aCGH；平铺在8q24以myc为中心。我们假定无论是顺式还是反式 放松监管，myc的异常促进了疾病的进展。我们已经发现，用一只小鼠 通过体细胞超突变并通过分析基因表达特征来引入myc激活的模型 在MM和MGUS中，myc去调控是疾病进展的候选机制。具体而言 目的3我们希望提供我们最初研究的患者的长期结果。我们将监测患者在 一种纵向的方式，将长期结果数据引入队列中已有的数据，并 还包括在具体目标1中确定的新标记。最后，在具体目标4中，我们想要做一个 MM与套细胞等成熟B细胞恶性肿瘤的比较基因组分析 淋巴瘤、边缘带淋巴瘤和沃尔登斯特龙巨球蛋白血症。套细胞淋巴瘤，比如MM， 股份细胞周期蛋白D上调(通常为d1，但偶尔也有d2和d3)为致病因素，如 1例MM边缘带淋巴瘤和Waldenstrom巨球蛋白血症具有相同的核因子-kB活性 说明MM有，并且，所有这些肿瘤都增强了对Bortezomib的反应性。

In this grant application we want to continue the search for markers causative and predictive of progression from MGUS to myeloma (MM). We previously established a reference cohort of patients in whom we have slides and samples to perform in situ single cell analysis. Since our last grant submission we have developed the expertise and published using the oligo based array comparative genomic hybridization (aCGH). We propose the following aims to better understand the cause of progression of MGUS to MM and to be able to predict better, so that a more appropriate counseling can occur with patients. Ultimately this information will be used for development of novel therapeutics. In Specific Aim 1 we wish to mine the existing genomic data on MM (both anatomic and functional) and to explore the possibility that some of the newfound markers are indeed progression events. We will subtract from these those already present in MGUS. We will test them as predictive markers, studying MGUS slides, and search for associations with existing baseline cytogenetic categories. In Specific Aim 2 we will explore the possibility that myc is a driver event in the progression to MM through a comprehensive genomic approach, including whole genome, high density, tiling aCGH; the tiling centered on myc at 8q24. We postulate that by either cis or trans deregulation, myc abnormalities contribute to the progression of the disease. We have found, using a murine model that introduces myc activation via somatic hypermutation, and by analysis gene expression signatures in MM and MGUS, that myc deregulation is a candidate mechanisms for disease progression. In Specific Aim 3 we wish to provide the long term outcome of patients initially studied by us. We.will monitor patients in a longitudinal fashion and will introduce the long-term outcome data to that already existing in the cohort and also include the novel markers identified in Specific Aim 1. Lastly, in Specific Aim 4 we would like to do a comparative genomic analysis between MM and other mature B-cell malignancies such as mantle cell lymphoma, marginal zone lymphoma and Waldenstrom macroglobulinemia. Mantle cell lymphoma, like MM, shares cyclin D upregulation (usually D1 but also occasionally D2 and D3) as a pathogenic, such as is the case in MM. Marginal zone lymphoma and Waldenstrom macroglobulinemia share the NF-kB activation state that MM has, and,all these tumors have enhanced responsiveness to bortezomib.