Oncogenic NOTCH Signaling: Mouse Modeling

我们的长期目标是了解失调的Notch信号在T细胞发病机制中的作用 并根据这些信息开发新的诊断、预后和治疗策略。 最近，Notch突变与超过一半的人类T-ALL有关，这表明 了解导致白血病的Notch信号的进展将对本病产生重大影响。完毕 在过去的十年里，我们开发了小鼠模型、组织培养试验和生化方法来 探讨Notch信号在T细胞白血病中的作用。在这里，我们将以这些发现为基础来确定 Notchl的突变形式是否会驱动异位T细胞发育并诱导小鼠白血病 将这些结果与不同Notchl等位基因对已定义的造血亚群的主要影响相关联 祖先。Notchl似乎有广泛的能力与许多其他转录产物合作 与人类T-ALL发育相关的因素。我们将确定这些突变的Notch等位基因的能力 与人类T-ALL中常见的其他基因协同作用，如Hox 11，Hox11L和Tall。 最后，Notchl的致白血病活性与未知下游靶点的上调有关 基因。利用一系列控制良好的表达谱实验和新型Notch依赖的T-ALL 对于T-ALL细胞系，我们将确定有助于T-ALL细胞持续生长的下游靶基因。 总之，这些研究将提供对Notch诱导的白血病发病机制的更深层次的了解， 从而使我们更接近于对这种疾病和其他病理状态进行新的治疗干预 以异常的Notch信号为特征。 这项建议的具体目标是： 1.确定新近发现的Notchl HD和/或PEST突变的转化能力 2.确定不同强度的Notchl信号如何与其他转录因子相互作用以诱导TALL 3.确定致癌Notchl促进转化的机制(S)

Our long term goal is to understand the role of dysregulated Notch signaling in the pathogenesis of T cell leukemia and to develop new diagnostic, prognostic, and therapeutic strategies based on this information. Recently, Notch mutations have been associated with more than half of human T-ALL, suggesting that advances in understanding leukemogenic Notch signaling will have a significant impact on this disease. Over the last decade, we have developed mouse models, tissue culture assays, and biochemical methods to investigate the role of Notch signaling in T cell leukemia. Here, we will build on these findings to determine whether mutant forms of Notchl drive ectopic T cell development and induce leukemias in mice, and will correlate these outcomes with primary effects of various Notchl alleles on defined subsets of hematopoietic progenitors. Notchl appears to have a broad capacity to collaborate with a number of other transcription factors linked to human T-ALL development. We will determine the ability of these mutated Notch alleles to synergize with other genes commonly implicated in human T-ALL, such as Hox 11, Hox11L and Tall. Finally, Notchl's leukemogenic activity has been linked to up-regulation of unknown downstream target genes. Using a series of well-controlled expression profiling experiments and novel Notch-dependent T-ALL cell lines, we will identify downstream target genes that contribute to the sustained growth of T-ALL cells. Together, these studies will provide a deeper understanding of the pathogenesis of Notch-induced leukemia, and thereby move us closer to novel therapeutic interventions in this disease and other pathologic states characterized by aberrant Notch signaling. The specific aims of this proposal are: 1. To determine the transforming ability of the recently identified Notchl HD and/or PEST mutations 2. To determine how Notchl signals of varying strength interact with other transcription factors to induce TALL 3. To determine the mechanism(s) by which oncogenic Notchl promotes transformation