The role of ETV6 in T-cell acute lymphoblastic leukemia

描述(申请人提供)：该项目旨在建立T细胞急性淋巴细胞白血病(T-ALL)中ETV6突变激活的致癌机制。我们的中心假设是，在T-ALL中发现的ETV6突变导致显性阴性ETV6亚型的表达，其表达扰乱了控制T细胞祖细胞中细胞增殖、分化和存活的特定转录调控网络。此外，我们认为ETV6突变与激活突变在T-ALL中EZH2的功能缺失和缺失中具有协同作用。因此，这项研究的目标是确定ETV6突变诱导的T-ALL的转录程序和致癌途径。为了实现这些目标，我们建议：(I)定义突变ETV6在T-ALL中控制的转录程序；以及(Iii)使用突变ETV6诱导T-ALL的小鼠模型来分析突变ETV6诱导转化的遗传学。

DESCRIPTION (provided by applicant): This project aims to establish the oncogenic mechanisms activated by ETV6 mutations in T- cell acute lymphoblastic leukemia (T-ALL). Our central hypothesis is that ETV6 mutations found in T- ALL result in expression of dominant negative ETV6 isoforms whose expression disrupts specific transcriptional regulatory networks that control cell proliferation, differentiation and survival in T-cell progenitor cells. In additin, we propose that ETV6 mutations cooperate with activating mutations in loss of function mutations and deletions in EZH2 in T-ALL. Thus, the goals of this research proposal are to define the transcriptional programs and oncogenic pathways responsible for the pathogenesis of mutant ETV6 induced T-ALL. To achieve these objectives we propose: (i) to define the transcriptional program controlled by mutant ETV6 in T-ALL; and (iii) to analyze the genetics of mutant ETV6 induced transformation using a mouse models of mutant ETV6 induced T-ALL.