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。其临床病程异质性大，难以预测；诊断后的总生存期（OS）差异很大（从<2年到数十年），因此这种预测至关重要。一些被诊断为Rai 0期（淋巴细胞增多症每L 5000个B淋巴细胞）或1期（淋巴细胞增多症伴淋巴结病）的患者不需要治疗；其他国家进展迅速。普遍接受的指南建议，只有在疾病进展（以贫血或淋巴结病等体征为特征）后才开始治疗。我们和其他人已经表明，蛋白质编码基因（PCGs）和非编码rna （ncRNAs）异常之间复杂的相互作用与CLL的起始和进展有因果关系。我们假设进展的风险与早期存在的CLL克隆的内在生物学特性（例如，来自恶性B细胞的PG或ncRNA的表达以及来自病毒起源）有关

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.