EXPLORATION OF NEUROBEACHIN (NBEA)'S ROLE IN MULTIPLE MYELOMA

描述（由申请人提供）：多发性骨髓瘤（MM）是美国第二常见的血液恶性肿瘤，是一种形态分化的浆b细胞恶性肿瘤，在很大程度上是不可治愈的。13号染色体缺失（del[13]）在大约一半（50%）的患者样本中发现，并且与较差的预后相关，但以前的努力未能最终确定13号染色体上的MM肿瘤抑制基因。我们使用了一种独特的超高分辨率阵列比较基因组杂交（aCGH）平台来分析MM患者样本，并确定了神经海滩蛋白（NBEA）是复发性间质缺失的新靶点。NBEA编码一种蛋白激酶a锚定蛋白（AKAP），该蛋白定位于反式高尔基体、转运囊泡和神经元突触后膜，在神经元细胞突触传递中发挥功能作用。我们的初步数据表明，NBEA不仅是13q13染色体缺失的靶标，而且NBEA在RNA和蛋白质水平上的表达在MM患者样本中显着失调。我们的假设是del[13]导致NBEA基因的失调，而NBEA的过表达导致MM疾病的进展。为了确定NBEA作为MM肿瘤标志物的潜在作用，我们提出以下目标：目的1：表征NBEA基因与MM疾病分期之间的关系。我们已经组装了一个独特的MM组织库，包括肿瘤和种系患者样本，我们将在MM患者样本中深入表征NBEA位点。我们将把NBEA基因型和表达数据与临床患者数据联系起来，并预测NBEA基因型将与MM的不良预后相关。目标2：开发新的检测MM患者样本中NBEA蛋白的方法。MM临床样品中NBEA蛋白的定量检测将为基于核酸的检测方法提供有用的辅助。我们将把NBEA蛋白水平与临床患者数据联系起来，并预计NBEA蛋白的高表达将与MM的不良预后相关。目的3：确定NBEA在MM疾病进展中的作用。基因定义的小鼠模型将用于明确地解决NBEA在骨髓瘤发展中的作用。我们的长期目标是在了解生殖系和体细胞遗传对MM疾病发展的贡献的基础上，开发新的疾病预防策略。公共卫生相关性：多发性骨髓瘤（MM）是美国第二大最常见的血液恶性肿瘤，约占所有血液肿瘤的10%。我们已经i)建立了一个独特的MM组织库，为基因研究提供关键工具；ii)开发了一个数据库，前瞻性地收集在Siteman综合癌症中心看到的MM患者的临床数据，这样我们就可以追踪分子异常到临床结果。我们已经确定NBEA是13号染色体上的一个新的候选基因，它是间质缺失的目标，其表达失调。我们将验证NBEA在MM中的作用，并将开发检测方法来表征MM临床标本中的NBEA。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, is a malignancy of morphologically differentiated plasma B-cells and is largely incurable. Chromosome 13 deletions (del[13]) are found in approximately one half (50%) of all patient samples and is associated with worse prognosis, but previous efforts have failed to conclusively identify the MM tumor suppressor gene on chromosome 13. We used a unique ultra high-resolution array comparative genomic hybridization (aCGH) platform to analyze MM patient samples, and identified neurobeachin (NBEA) as a novel target of recurrent interstitial deletions. NBEA encodes a protein kinase A anchoring protein (AKAP) that is localized to the trans-Golgi, transport vesicles and post-synaptic membranes of neurons where it plays a functional role in neuronal cell synaptic transmission. Our Preliminary Data demonstrated not only that NBEA is a target of chromosomal deletions at 13q13, but that NBEA expression at the RNA and protein level is significantly dysregulated in MM patient samples. Our hypothesis is that del[13] contributes to dysregulation of the NBEA gene, and that NBEA over- expression contributes to MM disease progression. To determine the potential role of NBEA as a tumor marker in MM, we propose the following aims: Aim 1: Characterize the relationship between the NBEA gene and MM disease stage. We have assembled a unique MM tissue bank with both tumor and germline patient samples, and we will characterize the NBEA locus in depth in our MM patient samples. We will correlate NBEA genotypes and expression data with clinical patient data, and anticipate that NBEA genotypes will be associated with poor outcomes in MM. Aim 2: Develop novel assays for NBEA protein detection in MM patient samples. Quantitative detection of NBEA protein in MM clinical samples will provide a useful adjunct to nucleic acid based detection methods. We will correlate NBEA protein levels with clinical patient data, and anticipate that high NBEA protein expression will be associated with poor outcomes in MM. Aim 3: Establish the role of NBEA in MM disease progression. Genetically defined murine models will be used to definitively address the role of NBEA in myeloma development. Our long-term goal is to develop novel disease prevention strategies based on understanding the genetic contribution, both germline and somatic, to MM disease development. PUBLIC HEALTH RELEVANCE: Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States accounting for approximately 10% of all hematologic neoplasms. We have i) established a unique MM tissue bank to provide critical tools for genetic studies and ii) have developed a database to prospectively collect clinical data on MM patients seen at the Siteman Comprehensive Cancer Center, so that we can trace molecular abnormalities back to clinical outcomes. We have identified NBEA as a novel candidate gene on chromosome 13 that is targeted by interstitial deletions and whose expression is dysregulated. We will validate the role of NBEA in MM and will develop assays to characterize NBEA in MM clinical specimens.