A NOVEL MECHANISM OF TCL1 TUMORIGENESIS

描述（由申请人提供）：我们提出了TCL1 （T细胞白血病-1）诱导淋巴样癌的新机制。假设异常的TCL1表达促进不适当的AKT（蛋白激酶- b）激活导致转化。然而，在B细胞中，tcl1增强的AKT激活程度与靶向删除PTEN肿瘤抑制因子诱导的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pten缺失小鼠从未形成B细胞癌。这些观察结果使我们假设tcl1介导的AKT增加最多具有轻微的致瘤作用。然而，我们不能排除TCL1改变AKT靶特异性的可能性，我们在本提案中简要地讨论了这一问题。

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.