A NOVEL MECHANISM OF TCL1 TUMORIGENESIS

TCL1肿瘤发生的新机制

• 批准号: 7213270
• 负责人: MICHAEL A TEITELL
• 金额: $ 27.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213270
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Antibodies; Antibody Specificity; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Binding; Cancer Etiology; Cell membrane; Chromosomal Rearrangement; Complex; Cytidine Deaminase; Dendritic Cells; Development; Enzymes; Family member; Gene Expression; Gene Family; Grouping; Healthcare; Hematologic Neoplasms; Hematopoietic Neoplasms; Histocompatibility Testing; Immune; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; In Vitro; Investigation; Knockout Mice; Lead; Ligands; Link; Lymphoid; Lymphoid Cell; Lymphomagenesis; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Messenger RNA; Minor; Myelogenous; Oncogenic; PTEN gene; Pathway interactions; Patients; Phosphotransferases; Polyribonucleotide Nucleotidyltransferase; Positioning Attribute; Process; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; RNA; Reaction; Reagent; Sampling; Specificity; Structure of germinal center of lymph node; System; T-Cell Leukemia; T-Cell Lymphoma; T-Cell Prolymphocytic Leukemia; T-Lymphocyte; TCL1B gene; Testing; Time; Tissues; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tumor Suppressor Proteins; Work; World Health Organization; base; carcinogenesis; cell growth; cell transformation; chronic T-cell leukemia; cohort; in vivo; lymphoid neoplasm; mouse model; novel; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): We propose a new mechanism for TCL1 (T cell leukemia-1) induction of lymphoid cancers. The assumption has been that aberrant TCL1 expression promotes inappropriate AKT (protein kinase-B) activation to cause transformation. However, the extent of TCL1-augmented AKT activation is comparable to the degree of enhanced AKT activation induced by targeted deletion of the PTEN tumor suppressor in B cells. Most notably, our TCL1 transgenic mice rapidly develop mature B cell malignancies while conditional PTEN-null mice never form B cell cancers. These observations lead us to hypothesize that TCL1-mediated AKT augmentation has, at most, a minor tumorigenic effect. We cannot, however, exclude the possibility that TCL1 alters the target specificity of AKT and we address this issue briefly in this proposal. Previously, we showed that a cytoplasmic membrane factor augmented TCL1/AKT interactions. We subsequently searched for new TCL1-interacting partners in flag-tagged TCL1 co-IP reactions. Surprisingly, we identified the RNA degrading enzyme polynucleotide phosphorylase (PNPase) as the sole TCL1 binding partner in lymphoid cells. We will determine whether or not PNPase is the TCL1/AKT interaction-augmenting factor. We favor the idea that PNPase/TCL1 interactions mediate TCL1-induced tumorigenesis through TCL1 stabilization of PNPase target mRNAs rather than by effecting AKT/TCL1 interactions. Testing this hypothesis is the main aim of this proposal. We provide preliminary evidence that TCL1/PNPase interactions block the processing of specific mRNAs. As such, TCL1 may be a natural PNPase ligand that regulates developmental gene expression by altering mRNA turnover by PNPase. When dysregulated, we predict TCL1 inappropriately stabilizes specific mRNAs destined for degradation, providing a novel mechanism of aberrant gene expression resulting in transformation. The most compelling candidate target mRNA is AID, since persistent AID hypermutation could account for the broad spectrum of germinal center-derived B cell cancers in our TCL1 transgenic mouse model. The specific aims in this proposal form an investigation of the mechanism of TCL1-mediated transformation, focusing on functional consequences of interactions between TCL1, PNPase and to a lesser extent AKT in vitro and in vivo.

描述（由申请人提供）：我们提出了一种 TCL1（T 细胞白血病-1）诱导淋巴癌的新机制。 假设异常的 TCL1 表达会促进不适当的 AKT（蛋白激酶 B）激活从而引起转化。 然而，TCL1 增强的 AKT 激活程度与 B 细胞中 PTEN 肿瘤抑制因子的靶向删除诱导的 AKT 激活增强程度相当。 最值得注意的是，我们的 TCL1 转基因小鼠迅速发展为成熟的 B 细胞恶性肿瘤，而条件性 PTEN 缺失小鼠则永远不会形成 B 细胞癌症。这些观察结果使我们推测 TCL1 介导的 AKT 增强至多具有较小的致瘤作用。 然而，我们不能排除 TCL1 改变 AKT 靶标特异性的可能性，我们在本提案中简要讨论了这个问题。 之前，我们发现细胞质膜因子增强了 TCL1/AKT 相互作用。 我们随后在标记的 TCL1 co-IP 反应中寻找新的 TCL1 相互作用伙伴。 令人惊讶的是，我们发现 RNA 降解酶多核苷酸磷酸化酶 (PNPase) 是淋巴细胞中唯一的 TCL1 结合伴侣。 我们将确定 PNPase 是否是 TCL1/AKT 相互作用增强因子。 我们赞成这样的观点，即 PNPase/TCL1 相互作用通过 TCL1 对 PNPase 靶标 mRNA 的稳定而不是通过影响 AKT/TCL1 相互作用来介导 TCL1 诱导的肿瘤发生。 检验这一假设是本提案的主要目的。 我们提供了 TCL1/PNPase 相互作用阻断特定 mRNA 加工的初步证据。因此，TCL1 可能是一种天然的 PNPase 配体，通过 PNPase 改变 mRNA 周转来调节发育基因表达。 当失调时，我们预测 TCL1 会不适当地稳定注定要降解的特定 mRNA，从而提供异常基因表达导致转化的新机制。 最引人注目的候选靶标 mRNA 是 AID，因为持续的 AID 超突变可以解释我们的 TCL1 转基因小鼠模型中广泛的生发中心衍生的 B 细胞癌症。 本提案的具体目标是研究 TCL1 介导的转化机制，重点关注 TCL1、PNPase 以及较小程度上 AKT 之间体外和体内相互作用的功能后果。