The role of ETV6 in T-cell acute lymphoblastic leukemia

ETV6在T细胞急性淋巴细胞白血病中的作用

• 批准号: 8421646
• 负责人: Adolfo A. Ferrando
• 金额: $ 33.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8421646
• 关键词: Accounting; Acute T Cell Leukemia; Address; Adult; Adult Acute Lymphocytic Leukemia; Affinity Chromatography; C-terminal; Cell Proliferation; Cell physiology; Childhood; Complex; Development; Disease Progression; Dominant-Negative Mutation; ETV6 gene; EZH2 gene; Early treatment; Family; Gene Expression Profile; Genetic; Genomics; Goals; Hematopoietic; Hematopoietic stem cells; Human; Induced Mutation; Lesion; Mediating; Molecular; Mus; Mutate; Mutation; N-terminal; NOTCH1 gene; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Protein Isoforms; Proteins; Proteomics; RUNX1 gene; Recurrence; Refractory Disease; Relapse; Research; Research Proposals; Role; Sampling; Somatic Mutation; Stem cells; T-Cell Transformation; T-Lymphocyte; Testing; Transcription Repressor/Corepressor; Transcriptional Regulation; Transferase; Transgenic Mice; Treatment Failure; Tumor Suppressor Genes; Tumor Suppressor Proteins; bone; chemotherapy; genetic analysis; in vivo; insight; leukemia; loss of function mutation; mutant; mutant mouse model; novel; outcome forecast; progenitor; programs; public health relevance; response; stem; t(8; 21)(q22; q22); tool; tumor

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.

描述（由申请人提供）：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 突变导致显性失活 ETV6 亚型的表达，其表达破坏了控制 T 细胞祖细胞增殖、分化和存活的特定转录调控网络。此外，我们提出 ETV6 突变与 T-ALL 中 EZH2 功能丧失突变和缺失的激活突变协同作用。因此，本研究计划的目标是确定负责突变 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，我们建议：（i）定义 T-ALL 中突变体 ETV6 控制的转录程序； (iii)使用突变型ETV6诱导的T-ALL小鼠模型来分析突变型ETV6诱导的转化的遗传学。