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

描述(申请人提供)：慢性淋巴细胞白血病(CLL)是西半球最常见的成人白血病。它的临床过程是不同的，很难预测；诊断后的总生存期(OS)差异很大(从两年到几十年)，这使得这样的预测至关重要。一些被诊断为RAI 0期(5,000个B淋巴细胞增多症/L)或1期(淋巴细胞增多症伴淋巴结病)的患者从不需要治疗；另一些进展很快。普遍接受的指南建议只有在疾病进展(表现为贫血或淋巴结病等症状)后才开始治疗。我们和其他人已经证明，蛋白质编码基因(PCGs)和非编码RNA(NcRNAs)异常之间的复杂相互作用在CLL的启动和进展中起着因果作用。我们假设进展的风险与早期存在的CLL克隆的固有生物学特征(例如，来自恶性B细胞的Pg或ncRNA的表达以及来自病毒的)有关 病程。因此，应该有可能区分有进展风险的患者和惰性CLL患者(定义为确诊后5年内不需要治疗的稳定的RAI 0/I期疾病)。被诊断为CLL的任何阶段的患者，在治疗前或治疗后，都可能经历里氏转化(RT)；他们发展为侵袭性弥漫性大B细胞淋巴瘤，典型的治疗耐药，并与短OS相关。大约80%-90%的RT与CLL克隆有关。我们假设发生RT的风险与转化前CLL克隆的固有生物学特性有关。因此，应该有可能在病程的早期识别那些有RT风险的患者。目前使用的临床标记物都不能很准确地做到这一点。该提案的目标是专注于这一具有挑战性的临床早期病例子集，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相互作用或成对的microRNA和靶向PCGs，在疾病的发生中发挥关键作用，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.