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

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是西半球成人中最常见的白血病。其临床过程是异质性的，难以预测;诊断后的总生存期（OS）差异很大（从<2年到数十年），使得这种预测至关重要。一些被诊断为Rai 0期（淋巴细胞增多症e5，000 B淋巴细胞/μ L）或1期（淋巴细胞增多症伴淋巴结病）的患者不需要治疗;其他患者进展迅速。普遍接受的指南建议仅在疾病进展后开始治疗（以贫血或淋巴结病等体征为特征）。我们和其他人已经表明，蛋白质编码基因（PCG）和非编码RNA（ncRNA）异常之间的复杂相互作用与CLL的发生和进展有因果关系。我们假设进展的风险与CLL克隆的内在生物学特征（例如来自恶性B细胞以及来自病毒来源的PG或ncRNA的表达）有关，该克隆存在于CLL的早期， 疾病的过程。因此，应该可以区分有进展风险的患者与惰性CLL患者（定义为诊断后e5年内不需要治疗的稳定Rai 0/I期疾病）。被诊断为任何阶段的CLL的患者，在治疗之前或之后，可能经历里希特转化（RT）;他们发展为侵袭性弥漫性大B细胞淋巴瘤，其通常具有治疗抗性并与短OS相关。约80-90%的RT与CLL克隆克隆相关。我们推测，发展RT的风险与转化前CLL克隆的内在生物学特征相关。因此，它应该是可能的，以确定这些患者谁是在RT的风险在疾病过程的早期。目前使用的临床标记物都不能以高准确度做到这一点。该提案的目标是关注临床早期病例的这一具有挑战性的子集，以确定编码和非编码RNA转录本的表达特征，阐明它们在疾病进展中的作用，以及它们作为早期诊断生物标志物的临床意义。我们的长期目标是找到在疾病发作中起关键作用的相互作用或成对的microRNA和靶向PCG，了解它们的作用机制，并利用获得的知识开发新的诊断和预后工具。

DESCRIPTION (provided by applicant): 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 PG 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 interact or 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.