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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：慢性淋巴细胞白血病 (CLL)，也称为小细胞淋巴瘤，几乎占所有非霍奇金淋巴瘤病例的 30%，尽管化疗方案取得了进展，但它是最常见的成人白血病。 CLL 患者的疗效有限，特别是对于 B 细胞受体 (BCR)、del (17p13.1) 和未突变类型的患者p53 突变是一种致癌基因，最初发现在 T 细胞白血病中易位，现已发现在被归类为侵袭性的 CLL 表型中表达水平较高。使用免疫球蛋白启动子和 E¿ 的 B 细胞中的 Tcl-1 癌基因这些小鼠在 13-18 个月内可重复发展 CLL，并已被证明是人类 CLL 的优秀模型。Par-4 是我们发现的一种促凋亡肿瘤抑制因子，可诱导癌症细胞凋亡，但不能诱导正常细胞凋亡。我们进行了四个新的观察：B 细胞受体信号通路在人类 CLL 细胞和 E¿ -通过 Src 家族蛋白酪氨酸激酶 (SFK) 的组成型激活反映 CLL 的 Tcl-1 小鼠模型其次，我们发现抑制 SFK 后 Tcl1 的表达下调，这表明 BCR 信号在 Tcl1 表达中发挥作用。发现 Par-4 的表达在 E¿ -Tcl1 CLL 细胞与正常小鼠相比，而其表达在人类 CLL 细胞中是可变的。第四，我们发现 E¿ -Tcl1 细胞被可溶性 Par-4 和 SAC 杀死，SAC 是 Par-4 的一个特定结构域，仅对肿瘤细胞具有细胞毒性。根据这些观察，我们发现受 BCR 信号传导调节的 Tcl1 和 Par-4 之间的平衡决定了细胞的命运。我们有三个具体目标，即确定 BCR 信号传导的重要性以及特定 SFK 在使用 E¿ 调节 Tcl-1 和 Par-4 表达中的作用。 -CLL 的 Tcl-1 小鼠模型。目标 2 将使用新生成的可诱导 Par-4 转基因小鼠模型和 E¿ 来研究 Par-4 过度表达对 CLL 发展的重要性。 -Tcl-1 小鼠将涉及临床前研究，以测试细胞外 Par-4 和 SAC 抑制 E¿ -Tcl-1 小鼠模型。目标 3 中将利用来自患者的原代 CLL 细胞研究 Tcl-1 和 Par-4 的相对重要性，从而将目标 1 和 2 中的基础研究结果转化为临床样本。 OSU 为我们提供了一个机会，将前两个目标的基础科学和临床前发现与使用患者来源的 CLL 细胞进行的目标 3 的研究相结合，这些研究令人兴奋的方面是可溶性 Par-4 或SAC 可以开发成 CLL 细胞的治疗策略，可以单独使用，也可以与 SFK 抑制剂或我们实验室目前正在研究的其他靶标联合使用。