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）：我们提出了一种新的TCL 1（T细胞白血病-1）诱导淋巴癌的机制。 假设是异常的TCL 1表达促进不适当的AKT（蛋白激酶-B）活化以引起转化。 然而，TCL 1增强的AKT活化程度与B细胞中靶向缺失PTEN肿瘤抑制因子诱导的增强的AKT活化程度相当。 最值得注意的是，我们的TCL 1转基因小鼠迅速发展成熟的B细胞恶性肿瘤，而条件性PTEN缺失小鼠从不形成B细胞癌。这些观察结果使我们假设TCL 1介导的AKT增强最多具有轻微的致瘤作用。 然而，我们不能排除TCL 1改变AKT靶特异性的可能性，我们在本提案中简要讨论了这个问题。 以前，我们表明，细胞质膜因子增强TCL 1/AKT的相互作用。 随后，我们在标记的TCL 1 co-IP反应中寻找新的TCL 1相互作用伙伴。 令人惊讶的是，我们确定了RNA降解酶多核苷酸磷酸化酶（PNIPs）作为淋巴细胞中唯一的TCL 1结合伴侣。 我们将确定PNDT是否是TCL 1/AKT相互作用增强因子。 我们支持这样的观点，即PNTR/TCL 1相互作用通过TCL 1稳定PNTR靶mRNA介导TCL 1诱导的肿瘤发生，而不是通过影响AKT/TCL 1相互作用。 检验这一假设是本提案的主要目的。 我们提供的初步证据表明，TCL 1/PNTR的相互作用阻止特定的mRNA的加工。因此，TCL 1可能是一种天然的PNIPs配体，通过改变PNIPs的mRNA周转来调节发育基因的表达。 当失调时，我们预测TCL 1会不适当地稳定注定要降解的特定mRNA，从而提供导致转化的异常基因表达的新机制。 最引人注目的候选靶mRNA是AID，因为持续的AID超突变可以解释我们的TCL 1转基因小鼠模型中的广泛的生发中心来源的B细胞癌。 本提案的具体目标是对TCL 1介导的转化机制进行研究，重点关注TCL 1、PND 3和AKT在体外和体内较小程度上相互作用的功能后果。