TOWARD AN UNDERSTANDING OF CLL PROGRESSION

了解 CLL 的进展

• 批准号: 8327710
• 负责人: CARLO M CROCE
• 金额: $ 37.5万
• 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/8327710
• 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.

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是人类白血病最常见的形式。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，惰性疾病会进展为侵袭性形式。因此，对该疾病的临床治疗方法是“等待和观察”，因为用积极的化疗/免疫疗法治疗惰性 CLL 患者可能会适得其反。 CLL 的特点是一致的染色体改变，其中最常见的是 13q14 缺失，细胞遗传学在超过 50% 的病例中观察到这种缺失。我们已经证明，这种缺失始终涉及两个 microRNA 基因：miR-15a 和 miR-16-1，这两个基因在大约 70% 的 CLL 患者中被敲除或下调。这些 microRNA 直接靶向 BCL2 并间接靶向 MCL1，这两个基因在 CLL 中失调。我们还发现 miR-15a 和 16-1 的缺失与该疾病的惰性形式的发展有关。 我们还通过 t(14;14)(q11;q32) 易位或 inv(14)(q11;32) 倒位克隆了负责幼淋巴细胞 T 细胞白血病发展的 TCL1 基因，然后表明该基因在人类 CLL 的侵袭性形式中过度表达。最近，我们构建了在B细胞中过表达人类TCL1基因的TCL1转基因小鼠模型。 TCL1转基因小鼠会发展出侵袭性的慢性淋巴细胞白血病（CLL），这种疾病与人类的这种疾病非常相似（如果不是完全一样的话）。 利用我们对 CLL 中 microRNA 失调的理解，我们还开发了两种惰性形式的小鼠模型。 我们建议使用我们的小鼠模型来识别参与人类 CLL（包括家族性 CLL）发病机制的多步骤过程中的大多数基因。这些研究的结果将与人类 CLL 的研究结果进行比较。 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 的新型 CLL 疗法。