P3 - Biology and Epidemiology of APRIL and Blys in B-cell and NHL

越来越多的证据表明，肿瘤坏死因子超家族成员布莱斯和阿普丽尔，如 以及它们的受体，作为正常和恶性B细胞生长和存活的关键因素。 BLyS和APRIL在B细胞性非霍奇金淋巴瘤(NHL)中均有表达，BLyS的表达 与侵袭性疾病表型有关。虽然很明显，BLyS表达对于 正常B细胞发育和动态平衡--BLyS在正常和恶性肿瘤中的确切来源 情景还有待充分阐明。因为在许多B细胞中，血清BLyS水平升高 已知有家族发病的恶性肿瘤，BLyS的调节失调可能发生在 遗传水平。调节BLyS表达的环境和遗传要求仍然存在 BLyS基因启动子的特征还不是很清楚。在初步工作中生成 从我们的UI/MC淋巴瘤孢子开发项目中，我们发现在 BLyS启动子区域与B细胞恶性肿瘤患者血清BLyS水平升高相关 尤其是那些有B细胞相关癌症家族史的人。我们现在建议跟进这些 通过一个新的、综合的基础科学和人口科学项目的发现，利用标本 和通过UI/MC淋巴瘤孢子生物检疫核心开发的流行病学资源 和分子流行病学资源(孢子项目5)在第一个项目期。我们 将确定BLyS、BLyS受体TACI、BCMA和BAFF-R是否也存在遗传变异 作为BLYS相关的肿瘤坏死因子APRIL，与血吸虫病的发生发展密切相关 患者的临床结果。除了我们的基因研究，我们还建议确定 APRIL在NHL B细胞生物学中的作用我们假设四月与增长有关。 和恶性B细胞的存活，认为它可能参与了NHL的发病机制。 确定有或倾向于BLyS和APRIL水平升高的患者，或那些 在BLyS或他们的受体中有基因改变，将为我们提供一个更好的机会 了解这些分子在B细胞恶性肿瘤中的意义，并最终翻译这些 这一发现有助于改进临床管理，或许还有新的治疗方法。

There is accumulating evidence that implicate the TNF superfamily members BLyS and APRIL, as well as their receptors, as critical factors for the growth and survival of both normal and malignant B cells. BLyS and APRIL are expressed in B-cell non-Hodgkin lymphoma (NHL) and the expression of BLyS is associated with an aggressive disease phenotype. While it is clear that BLyS expression is required for normal B cell development and homeostasis, the exact source of BLyS in the normal and malignant scenario remains to be fully elucidated. Because serum BLyS levels are elevated in a number of B cell malignancies known to have a familial incidence, it is possible that dysregulation of BLyS occurs at the genetic level. The environmental, as well as genetic, requirements that mediate BLyS expression remain to be defined, and the promoter for the BLyS gene is poorly characterized. In preliminary work generated from our UI/MC Lymphoma SPORE Developmental Projects, we have found that a polymorphism in the BLyS promoter region correlates with increased serum BLyS levels in patients with B-cell malignancies, particularly those with a family history of B-cell related cancers. Wenow propose to follow-up these findings through a new,integrated basic andpopulation science project that utilizes the specimen and epidemiology resources developed through the UI/MC Lymphoma SPORE Biospecimens Core and the Molecular Epidemiology Resource(SPORE Project 5)during the first project period. We will determine if genetic variability in BLyS, the BLySreceptors TACI, BCMA, and BAFF-R, as well as the BLySrelated TNF molecule APRIL, are associatedwith the development of NHLand the clinical outcomeof patients. In addition to our genetic studies, wealso propose to determine the role of APRIL on thebiology of NHL B cells. We hypothesize that APRIL is involvedin the growth and survival of malignant B cells andbelieve that it maycontribute to thepathogenesis of NHL. Identification of patients who have or are predisposed to elevated BLyS and APRIL levels, or those who have genetic alterations in BLyS, APRIL, or their receptors, will provide us with an opportunity to better understand the significance of these molecules in B cell malignancies and ultimately to translate these findings to improved clinical management and perhaps novel therapeutic approaches.