Role of CLUS in Multistep Pathogenesis of Familial CLL

CLUS 在家族性 CLL 多步发病机制中的作用

• 批准号: 6869044
• 负责人: MARTHA J GLENN
• 金额: $ 13.46万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-11 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869044
• 关键词: biomarker; cancer registry /resource; cancer risk; carcinogenesis; chromosome aberrations; chronic lymphocytic leukemia; clinical research; early diagnosis; family genetics; flow cytometry; genetic susceptibility; human subject; linkage mapping; lymphocytosis; neoplasm /cancer epidemiology; preneoplastic state

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the U.S., and there is an increased incidence among relatives of affected patients (familial CLL). Although the etiology of CLL is unknown, several recurrent cytogenetic abnormalities have been described. Recent reports suggest low numbers of CLL-phenotype cells can be detected in 3.5% of healthy adults by flow cytometry, with a striking 4-fold greater frequency in relatives of patients with familial CLL, a detection rate of 13.5%. Because little is known about these cells, the term "clonal lymphocytosis of unknown significance" (CLUS) has been applied. We hypothesize that development of familial CLL is a stepwise process that includes an initial, inherited abnormality that increases chromosomal instablility in B lymphocytes. This may lead to additional mutations in genes that contribute to the accumulation of these abnormal cells, manifested initially by CLUS. Subsequent events may then lead to the development of clinical CLL. To begin to study this process, we will utilize the Utah Population Database to identify CLL families, and a Utah Familial CLL Registry will be established. This will include participants known to have CLL and unaffected relatives. Since the nature of the underlying predisposing genetic abnormality may be reflected in clinical characteristics of these familial CLL cases, we will analyze clinical, immunophenotypic and molecular factors to comprehensively characterize familial CLL and carefully compare to sporadic CLL Furthermore, the peripheral blood lymphocytes of the unaffected members will be analyzed for CLUS cells to determine the prevalence of CLUS in the Utah families. These CLUS cells will be isolated for biological and molecular studies including antigen expression important for CLL prognosis, such as CD 38 and ZAP-70, and assessment of chromosomal abnormalities detectable by fluorescence in situ hybridization. Finally, the structure and phenotypic characteristics of these families will allow for simulation of linkage analysis strategies for planned investigation of the underlying gene(s) responsible for this predisposition. Ultimately, we anticipate that this insight into the multi-step pathway leading to CLL will lead to better detection and prediction of risk of development of CLL, possible early intervention to change the natural history of the disease, and identification of new therapeutic targets.

慢性淋巴细胞白血病（CLL）是美国最普遍的成年白血病，受影响患者的亲属（家族性CLL）的发病率增加。尽管CLL的病因尚不清楚，但已经描述了几种复发性的细胞遗传学异常。最近的报道表明，通过流式细胞仪，可以在3.5％的健康成年人中检测到CLL-表型细胞数量少，而家族性CLL患者的亲属的频率更高，其检测率为13.5％。由于对这些细胞知之甚少，因此已经应用了“克隆淋巴细胞增多”一词（CLUS）。我们假设家族性CLL的发展是一个逐步过程，其中包括一个初始的，遗传的异常，可增加B淋巴细胞中染色体的不稳定性。这可能会导致其他突变 在有助于这些异常细胞积累的基因中，最初由CLU表现出来。 然后随后的事件可能导致临床CLL的发展。为了开始研究这一过程，我们将利用犹他州人口数据库来识别CLL家族，并将建立犹他州的CLL注册表。这将包括已知有CLL和不受影响的亲戚的参与者。由于潜在的遗传异常的性质可以反映在这些家族性CLL病例的临床特征上，因此我们将分析临床，免疫非型和分子因素，以全面地表征家族性的CLL，并仔细地表征与偶发性CLL相比，将其与外围血液的过度分析，分析lymphocpytes的过度分析是分析的。在犹他州家庭。这些clus细胞将被分离用于生物学和分子研究 抗原表达对CLL预后很重要，例如CD 38和ZAP-70，并评估 通过荧光原位杂交可检测到的染色体异常。最后，这些家族的结构和表型特征将允许模拟链接分析策略，以计划对负责这种倾向的基础基因进行研究。最终，我们预计，对导致CLL的多步途径的这种洞察力将导致更好地发现和预测CLL发展风险，可能早期干预以改变疾病的自然史以及对新的治疗靶标的识别。