TOWARD AN UNDERSTANDING OF CLL PROGRESSION

了解 CLL 的进展

• 批准号: 8108375
• 负责人: CARLO M CROCE
• 金额: $ 37.52万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108375
• 关键词: 11q23; 13q14; 15q23; 17p13; 19q13.32; 2p13; 2q37.1; 6p25.3; Affect; Age; Age-Months; Age-Years; Aggressive course; B-Lymphocytes; BCL2 gene; Cells; Characteristics; Chromosome abnormality; Chronic Lymphocytic Leukemia; Clinical; Cytogenetics; Defect; Development; Disease; Disease Progression; Early treatment; Epigenetic Process; Event; Gene Expression Alteration; Genes; Genetic; Genomics; Goals; Human; Immunoglobulin M; Immunotherapy; Individual; Indolent; Knock-out; Knockout Mice; Life; Lymphocyte; MCL1 gene; Malignant - descriptor; MicroRNAs; Modeling; Mus; Mutation; Oncogenes; Pathogenesis; Patients; Process; Receptors, Antigen, B-Cell; Risk Factors; Surface; T-Cell Leukemia; T-Cell Prolymphocytic Leukemia; T-Lymphocyte; Testing; Therapeutic; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Transplantation; aggressive therapy; base; chemotherapy; genome wide association study; high risk; inv(14); knock-down; leukemia; mouse model; novel; overexpression; protein expression; t(14; 14)(q11; q32); tumor; tumor progression

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most common form of human leukemia. It affects individuals over 50 years of age and it manifests either as an indolent or an aggressive disease. Often, with time, the indolent disease progresses to the aggressive form. Thus, the clinical approach to the disease is "wait and watch", since it may be counterproductive to treat patients with indolent CLL with aggressive chemo/immunotherapy. CLL is characterized by consistent chromosomal alterations, the most common of which is a deletion at 13q14 that is observed by cytogenetics in over 50% of cases. We have shown that this deletion consistently involves two microRNA genes, miR-15a and miR-16-1, which are knocked out or down in approximately 70% of CLL patients. These microRNAs target directly BCL2 and indirectly MCL1, two genes dysregulated in CLL. We also found that loss of miR-15a and 16-1 is associated with the development of the indolent form of the disease. We have also cloned the TCL1 gene responsible for the development of prolymphocytic T cell leukemia through t(14;14)(q11;q32) translocations or inv(14)(q11;32) inversions and then shown that this gene is overexpressed in the aggressive form of human CLL. Recently, we have constructed a TCL1 transgenic mouse model that overexpresses the human TCL1 gene in B cells. TCL1 transgenic mice develop the aggressive form of CLL that resembles quite closely, if not exactly, the human form of the disease. We also developed two mouse models for the indolent form of the disease by taking advantage of our understanding of microRNA dysregulation in CLL. We propose to use our mouse models to identify most of the genes involved in the multistep process responsible for the pathogenesis of human CLL, including familial CLL. The results of these studies will be compared to those in human CLLs. By taking advantage of our new mouse models, we also propose to develop novel microRNA-based therapies for CLL by targeting the expression of critical oncogenes. PUBLIC HEALTH RELEVANCE: We propose to identify genetic and epigenetic changes responsible for the progression of chronic lymphocytic leukemia (CLL), the most common human leukemia. To achieve our goal, we have developed mouse CLL models that recapitulate the changes observed in human CLL. We propose to use these mouse models to identify the critical changes responsible for CLL progression and to develop novel targeted therapies for this incurable disease.

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是人类白血病的最常见形式。它影响50岁以上的个体，表现为惰性或侵袭性疾病。通常，随着时间的推移，惰性疾病进展为侵袭性形式。因此，该疾病的临床方法是“等待和观察”，因为用积极的化疗/免疫疗法治疗惰性CLL患者可能适得其反。 CLL的特征在于一致的染色体改变，其中最常见的是在13 q14处的缺失，其在超过50%的病例中通过细胞遗传学观察到。我们已经证明，这种缺失始终涉及两个microRNA基因，miR-15 a和miR-16-1，它们在大约70%的CLL患者中被敲除或下调。这些microRNA直接靶向BCL 2和间接靶向MCL 1，这两个基因在CLL中失调。我们还发现，miR-15 a和16-1的缺失与疾病的惰性形式的发展有关。 我们还克隆了通过t（14;14）（q11;q32）易位或inv（14）（q11;32）倒位导致幼淋巴细胞性T细胞白血病发展的TCL 1基因，然后表明该基因在侵袭性人类CLL中过表达。最近，我们已经构建了一个TCL 1转基因小鼠模型，在B细胞中过表达人TCL 1基因。TCL 1转基因小鼠发展出侵袭性的CLL，即使不完全相似，也与人类的CLL非常相似。 我们还利用我们对CLL中microRNA失调的理解，开发了两种惰性形式疾病的小鼠模型。 我们建议使用我们的小鼠模型，以确定大多数的基因参与的多步骤的过程中负责的发病机制，人类慢性淋巴细胞白血病，包括家族性慢性淋巴细胞白血病。这些研究的结果将与人类CLL的结果进行比较。 通过利用我们的新小鼠模型，我们还建议通过靶向关键癌基因的表达来开发基于microRNA的CLL新疗法。 公共卫生相关性：我们建议确定慢性淋巴细胞白血病（CLL），最常见的人类白血病的进展负责的遗传和表观遗传的变化。为了实现我们的目标，我们已经开发了小鼠CLL模型，其概括了在人类CLL中观察到的变化。我们建议使用这些小鼠模型来确定导致CLL进展的关键变化，并为这种不治之症开发新的靶向治疗方法。