TOWARD AN UNDERSTANDING OF CLL PROGRESSION

描述(申请人提供)：慢性淋巴细胞白血病(CLL)是人类最常见的白血病类型。它影响50岁以上的人，要么表现为惰性疾病，要么表现为侵袭性疾病。通常，随着时间的推移，这种惰性疾病会发展成侵袭性的形式。因此，临床上对这种疾病的治疗方法是“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以持续的染色体改变为特征，其中最常见的是13q14处的缺失，细胞遗传学观察到这种缺失在50%以上。我们已经证明，这种缺失持续涉及两个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microRNAs直接针对BCL2和间接针对MCL1，这两个基因在CLL中调节异常。我们还发现miR-15a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)倒位导致前淋巴细胞T细胞白血病发生的TCL1基因，并证明该基因在人CLL的侵袭性形式中过表达。最近，我们构建了在B细胞中高表达人TCL1基因的TCL1转基因小鼠模型。TCL1转基因小鼠发展出侵袭性的CLL，即使不是完全相似，也非常类似于人类的CLL。我们还利用我们对CLL中microRNA失调的理解，开发了两种针对这种疾病的惰性形式的小鼠模型。我们建议使用我们的小鼠模型来确定与人类CLL发病相关的多步骤过程中的大多数基因，包括家族性CLL。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。

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.