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(申请人提供)：我们提出了一种新的T细胞白血病-1(T细胞白血病-1)诱导淋巴系肿瘤的机制。假设TCL1的异常表达促进了不适当的AKT(蛋白激酶-B)激活，从而导致转化。然而，TCL1增强的AKT激活的程度与靶向缺失PTEN肿瘤抑制因子在B细胞中诱导的AKT激活增强的程度相当。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缺失的小鼠永远不会形成B细胞癌症。这些观察结果使我们假设，TCL1介导的AKT增强至多具有轻微的致瘤作用。然而，我们不能排除TCL1改变AKT的靶标特异性的可能性，我们在本提案中简要地讨论了这个问题。 在此之前，我们已经证明了细胞质膜因子增强了TCL1/AKT的相互作用。随后，我们在标志标记的TCL1共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结合伙伴。我们将确定PNPase是否是TCL1/AKT相互作用的增强因子。我们支持这样的观点，即PNPase/TCL1的相互作用通过稳定PNPase靶基因的TCL1而不是通过影响AKT/TCL1的相互作用来介导TCL1诱导的肿瘤发生。检验这一假说是这一提议的主要目的。 我们提供了TCL1/PNPase相互作用阻止特定mRNAs处理的初步证据。因此，TCL1可能是一种天然的PNPase配体，通过改变PNPase的mRNA周转来调节发育基因的表达。当失控时，我们预测TCL1不适当地稳定特定的mRNAs注定要降解，提供了一种新的机制，异常基因表达导致转化。最引人注目的候选靶基因是AID，因为在我们的TCL1转基因小鼠模型中，持续的AID超突变可以解释生发中心衍生的广泛B细胞癌的原因。这项建议的具体目的是研究TCL1介导的转化机制，重点是TCL1、PNPase和较小程度的AKT在体内外相互作用的功能后果。