The role of ETV6 in T-cell acute lymphoblastic leukemia

项目描述（申请人提供）：本项目旨在建立T细胞急性淋巴细胞白血病（T- all）中由ETV6突变激活的致瘤机制。我们的中心假设是，在T- ALL中发现的ETV6突变导致显性负ETV6亚型的表达，其表达破坏了T细胞祖细胞中控制细胞增殖、分化和存活的特异性转录调节网络。此外，我们提出ETV6突变与激活突变合作，导致T-ALL中EZH2的功能丧失突变和缺失。因此，本研究计划的目标是确定突变型ETV6诱导T-ALL发病机制的转录程序和致癌途径。为了实现这些目标，我们提出：(i)确定T-ALL中由突变体ETV6控制的转录程序；（iii）利用突变体ETV6诱导T-ALL小鼠模型分析突变体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.