Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia

Tcl1和Par-4在慢性淋巴细胞白血病的调节中的作用

• 批准号: 8440656
• 负责人: SUBBARAO BONDADA
• 金额: $ 39.3万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-07 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440656
• 关键词: 17p13.1; A Mouse; Affect; Animal Model; Apoptosis; Apoptotic; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Basic Science; Biology; Bone Marrow; Cell Aging; Cell Survival; Cells; Cessation of life; Chromosomal translocation; Chronic Lymphocytic Leukemia; Clinical; Clinical Data; Clinical Investigator; Clinical Trials; Collaborations; Development; Disease; Down-Regulation; Elderly; Enhancers; Equilibrium; Family; Family member; GRP gene; GRP78 gene; Genes; Genetic; Goals; Grant; Growth; Human; Immunoglobulins; In Vitro; Induction of Apoptosis; Laboratories; Leukemic Cell; Lymphoid; Malignant Neoplasms; Mediating; Modality; Modeling; Mus; Mutation; Nature; Non-Hodgkin' s Lymphoma; Normal Cell; Oncogenes; Organ; PAWR gene; Pathway interactions; Patients; Peptides; Phenotype; Play; Predisposition; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Relative (related person); Resistance; Role; Sampling; Signal Pathway; Signaling Molecule; Small Interfering RNA; Small-Cell Lymphoma; Surface; T-Cell Leukemia; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Transcription Factor AP-1; Transgenic Mice; Transgenic Organisms; Translating; Tumor Suppressor Proteins; Western World; Whole Blood; adult leukemia; base; cancer cell; cell age; cell killing; chemotherapy; clinically relevant; cytotoxic; efficacy testing; extracellular; in vivo; inhibitor/antagonist; killings; member; molecular marker; mouse model; neoplastic cell; novel; outcome forecast; overexpression; peripheral blood; pre-clinical; preclinical study; pro-apoptotic protein; promoter; public health relevance; receptor; response; therapy development; transcription factor; treatment strategy; tumor

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL), also known as small cell lymphoma, constitutes almost 30% of all cases of non-Hodgkin's lymphoma. It is the most common adult leukemia. Despite advances in chemotherapy, treatment options for CLL patients are limited with only a modest efficacy, especially for patients with unmutated types of B cell receptors (BCR), del (17p13.1) and p53 mutations. Tcl-1, an oncogene, initially found to be translocated in T-cell leukemias, has been found to be expressed at higher levels in CLL phenotypes that are classified as aggressive. A mouse model for CLL has been generated by expressing the Tcl-1 oncogene in B cells using immunoglobulin promoter and the E¿ enhancer. These mice reproducibly develop CLL in 13-18 months and have been shown to be excellent models for human CLL. Par-4 is a pro-apoptotic tumor suppressor, discovered by us, that induces apoptosis in cancer but not normal cells using both the Fas pathway and by inhibiting NF-?B. We made four novel observations. First, the B-cell receptor signaling pathway is active both in the human CLL cells and in the E¿-Tcl-1 mouse model of CLL as reflected by constitutive activation of Src family protein tyrosine kinases (SFK). Second, we discovered that expression of Tcl1 is down regulated upon inhibition of SFK suggesting a role for BCR signaling in Tcl1 expression. Third we found that expression of Par-4 is down-regulated in E¿-Tcl1 CLL cells compared to normal mice, while its expression has been found to be variable in human CLL cells. Fourth we discovered that E¿-Tcl1 cells are killed by soluble Par-4 and SAC, a specific domain of Par-4 that is cytotoxic only to tumor cells. Based on these observations we hypothesize that a balance between Tcl1 and Par-4 regulated by BCR signaling decides the fate of CLL cells between survival and death. We have three specific aims. Aim 1 will determine the importance of BCR signaling and the role of specific SFKs in the regulation of Tcl-1 and Par-4 expression using the E¿-Tcl-1 mouse model of CLL. Aim 2 will investigate the importance of Par-4 overexpression for CLL development using a newly generated inducible Par-4 transgenic mice mouse model and the E¿-Tcl-1 mice. Aim 2 will involve preclinical studies to test the efficacy of extracellular Par-4 and SAC to inhibit CLL growth in the E¿-Tcl-1 mouse model. The relative importance of Tcl-1 and Par-4 will be studied in Aim 3 with primary CLL cells from patients, thus translating the basic research findings in Aims 1 and 2 to clinical samples. The collaboration between UK and OSU provides us an opportunity to integrate the basic science and pre-clinical findings from the first two Aims with studies in Aim 3 using patient derived CLL cells. The exciting aspect of these studies is the possibility that soluble Par-4 or SAC can be developed into a treatment strategy for CLL cells either in isolation or in combination with SFK inhibitors or other targets that are currently being investigated in our laboratories.

描述（由适用提供）：慢性淋巴细胞性白血病（CLL），也称为小细胞淋巴瘤，几乎占非霍奇金淋巴瘤的所有病例的30％。它是最常见的成年白血病。尽管化学疗法进展，但CLL患者的治疗选择仅受效率适度的限制，尤其是对于未经物质的B细胞受体（BCR），DEL（17p13.1）和p53突变的患者。 TCL-1是一种最初发现在T细胞白血病中翻译的癌基因，在CLL表型中以较高的水平表达，这些表型被归类为侵略性。通过使用免疫球蛋白启动子和E e升增强剂表达B细胞中的TCL-1癌基因，已经产生了用于CLL的小鼠模型。这些小鼠在13-18个月内可重复发展CLL，已被证明是人类CLL的出色模型。 PAR-4是我们发现的促凋亡肿瘤抑制剂，它使用FAS途径并抑制NF-？B。我们进行了四个新颖的​​观察。首先，B细胞受体信号通路在人类CLL细胞和CLL的e-TCL-1小鼠模型中都活跃，这是由SRC家族蛋白酪氨酸激酶（SFK）的本构激活所反映的。其次，我们发现在抑制SFK的情况下，TCL1的表达受到调节，这表明BCR信号在TCL1表达中起作用。第三我们发现，与正常小鼠相比，在E tcl1 CLL细胞中，PAR-4的表达被下调，而其表达在人类CLL细胞中的表达是可变的。第四，我们发现e tcl1细胞被固体PAR-4和SAC杀死，固体PAR-4和SAC是PAR-4的特定结构域，仅对肿瘤细胞是细胞毒性的。基于这些观察结果，我们假设由BCR信号调节的TCL1和PAR-4之间的平衡决定了生存和死亡之间CLL细胞的命运。我们有三个具体的目标。 AIM 1将确定BCR信号传导的重要性以及特定SFK在使用CLL的E�-TCL-1小鼠模型的TCL-1和PAR-4表达调节中的作用。 AIM 2将使用新生成的诱导型PAR-4转基因小鼠模型和e e e。-TCL-1小鼠研究PAR-4过表达对CLL发育的重要性。 AIM 2将涉及临床前研究，以测试细胞外PAR-4和SAC的效率，以抑制E欧TCL-1小鼠模型中CLL生长的效率。 TCL-1和PAR-4的相对重要性将在AIM 3中与患者的原代CLL细胞一起研究，从而将AIM 1和2中的基础研究结果转化为临床样品。英国与OSU之间的合作为我们提供了一个机会，将前两个目的的基础科学和临床前发现与使用患者衍生的CLL细胞中的AIM 3研究相结合。这些研究的令人兴奋的方面是，可以将实体PAR-4或SAC发展为孤立或与SFK抑制剂或当前在我们实验室中正在研究的其他靶标结合使用的CLL细胞的治疗策略。