Protein-coding and non-coding RNA biomarkers for early detection of CLL

摘要 慢性淋巴细胞白血病（CLL）是西方国家成人中最常见的白血病。 半球其临床过程是异质性的，难以预测; 诊断差异很大（从<2年到几十年），使这种预测的最大 重要性一些患者被诊断为Rai 0期（淋巴细胞增多症e5，000 B淋巴细胞/L） 或1（淋巴细胞增多伴淋巴结病）不需要治疗;其他人进展迅速。一般 公认的指南建议仅在疾病进展后开始治疗（特征为 贫血或淋巴结病的发展，以及其他体征）。我们和其他人已经证明， 蛋白质编码基因（PCG）和非编码RNA异常之间的复杂相互作用 非编码RNA（ncRNA）与CLL的起始和进展有因果关系。我们假设 进展与内在生物学特征（例如PCG或ncRNA的表达）相关 来自恶性B细胞以及来自病毒来源）的CLL克隆，该克隆存在于 病程。因此，应该可以区分有进展风险的患者 来自惰性CLL患者（定义为不需要e5治疗的稳定Rai 0/I期疾病 诊断后10年）。在治疗前或治疗后诊断为任何阶段的CLL的患者， 经历里希特转化（RT）;他们发展为侵袭性弥漫性大B细胞淋巴瘤 约80-90%的RT与克隆相关， CLL克隆我们假设发生RT的风险与内在的 转化前CLL克隆的生物学特性。因此，应该能够 在病程早期识别出那些有RT风险的患者。没有一件礼物是用过的 临床标记物可以以高准确度完成这一点。本提案的目标是关注这一点 具有挑战性的临床早期病例子集，以识别编码的表达特征 和非编码RNA转录本，阐明它们在疾病进展中的作用，以及它们的临床 作为早期诊断的生物标志物的意义。我们的长期目标是找到相互作用对， microRNA和靶向PCG在疾病发作中起关键作用，了解它们的机制， 行动，并利用获得的知识，开发新的诊断和预后工具。

ABSTRACT Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western hemisphere. Its clinical course is heterogeneous and difficult to predict; overall survival (OS) after diagnosis varies considerably (from <2 years to decades), making such predictions of utmost importance. Some patients diagnosed with Rai stage 0 (lymphocytosis of e5,000 B lymphocytes/¿L) or 1 (lymphocytosis with lymphadenopathy) never need treatment; others progress rapidly. Generally accepted guidelines recommend starting treatment only after disease progression (characterized by development of anemia, or lymphadenopathy, among other signs). We and others have shown that an intricate interplay between abnormalities in protein-coding genes (PCGs) and non-coding RNAs (ncRNAs) is causally involved in CLL initiation, and progression. We hypothesize that the risk of progression is related to intrinsic biologic characteristics (e.g. expression of PCG or ncRNA from malignant B cells as well as from viral origin) of the CLL clone that exists early in the disease course. Thus, it should be possible to distinguish patients who are at risk of progression from patients with indolent CLL (defined as stable Rai stage 0/I disease not requiring therapy for e5 years after diagnosis). Patients diagnosed with any stage of CLL, before or after treatment, may undergo a Richter's transformation (RT); they develop an aggressive diffuse large B-cell lymphoma that is typically therapy resistant and associated with short OS. About 80-90% of RT is clonally related to the CLL clone. We hypothesize that the risk to develop RT is associated with intrinsic biologic characteristics of the CLL clone before transformation. Thus, it should be possible to identify those patients who are at risk of RT early in the disease course. None of the present used clinical markers can do this with high accuracy. This proposal's goal is to focus on this challenging subset of clinically early stage cases to identify expression signatures of coding and non-coding RNA transcripts, elucidate their roles in disease progression, and their clinical significance as biomarkers of early diagnosis. Our long-term goal is to find interactor pairs of microRNAs and target PCGs with key roles in the onset of disease, understand their mechanisms of action, and use the acquired knowledge to develop new diagnostic and prognostic tools.