MUTANT AND WILD TYPE WT1 IN AML

AML 中的突变型和野生型 WT1

• 批准号: 9763497
• 负责人: MATTHEW CHRISTOPHER
• 金额: $ 13.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763497
• 关键词: AML1-ETO fusion protein; Academic Medical Centers; Academic support; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Acute leukemia; Adult; American Society of Hematology; Award; Binding; Biological Assay; Biological Models; Bone Marrow; CBFA2T1 gene; CD34 gene; CRISPR/Cas technology; Cells; Chimeric Proteins; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Development; Disease; Disease Progression; Family; Frameshift Mutation; Future; Genes; Goals; Growth; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Human; Immunodeficient Mouse; Knock-in Mouse; Lentivirus Vector; Leukemic Cell; MLL-AF9; Malignant - descriptor; Mediating; Mentors; Messenger RNA; Minor; Modeling; Molecular; Mus; Mutation; Myelogenous; Pathogenesis; Patient Care; Physicians; Play; Program Development; RARA gene; RNA Splicing; RUNX1 gene; Research; Research Personnel; Research Project Grants; Resources; Retroviridae; Role; Sampling; Scientist; System; Tamoxifen; Testing; Therapeutic Agents; Tissues; Transgenic Organisms; Transplant Recipients; Transplantation; Tumor Suppressor Proteins; Umbilical Cord Blood; Universities; Variant; WT1 gene; Washington; Zinc Fingers; actionable mutation; acute myeloid leukemia cell; cancer genomics; career; career development; cellular transduction; design; experimental study; fusion gene; interest; leukemia; leukemogenesis; loss of function; loss of function mutation; mouse model; mutant; neurotensin mimic 1; novel therapeutic intervention; overexpression; prevent; response; retroviral-mediated; self-renewal; therapeutic evaluation; therapeutic target; transcription factor; virtual

Project summary/abstract This proposal describes a 5-year career development program designed to support an academic, physician- scientist career. The proposed research project will capitalize on the expertise and resources available at Washington University in St. Louis, which has a long tradition of developing physician-scientists. Dr. Timothy Ley, an expert in myeloid development and cancer genomics and a recipient of the American Society of Hematology Mentor Award, will serve as the research mentor. The ultimate goal of the candidate is to be an independent investigator in an academic medical center, studying normal and malignant hematopoiesis and taking care of patients with hematologic diseases. The experiments outlined in this application aim to clarify the role of wild type and mutant WT1 in Acute myeloid leukemia (AML) progression, with the goal to create new therapeutic approaches for this disease. Wilms tumor 1 (WT1) is a zinc-finger family transcription factor that is highly expressed in AML cells compared to normal hematopoietic progenitor cells, consistent with a possible role in promoting AML development and leading to considerable clinical interest in WT1 as a therapeutic target. Paradoxically, loss-of-function mutations in WT1 are also found in a subset of AML cases, raising the possibility that WT1 may promote or inhibit development of leukemia depending on the molecular context. Our lab recently performed preliminary studies suggesting that when co-occurring with the PML-RARA fusion, WT1 inhibits leukemic progression and self-renewal in a mouse model, suggesting that in this setting WT1 may prevent or delay leukemic progression. To reconcile the seemingly contradictory role of WT1 in AML progression we developed the following hypothesis to be tested in this proposal: WT1 expression is triggered in hematopoietic progenitors as a defensive response to AML-associated driver mutations. While fully transformed AML has developed means to overcome this inhibition, subsequent loss-of function mutations in WT1 provide a growth advantage to mutant subclones. Consistent with this hypothesis, we recently found that WT1 mRNA is induced 10-fold in CD34+ cells that have been transduced with several canonical AML-associated fusion genes. In this proposal, we will extend these observations to test whether overexpression or loss-of-function of WT1 can cooperate with these AML-associated mutations in mouse and human systems.

项目概要/摘要 该提案描述了一个为期5年的职业发展计划，旨在支持学术，医生- 科学家生涯拟议的研究项目将利用现有的专业知识和资源， 圣路易斯的华盛顿大学有着培养医学科学家的悠久传统。蒂莫西博士 Ley博士是骨髓发育和癌症基因组学专家，也是美国癌症协会的接受者。 血液学导师奖，将担任研究导师。候选人的最终目标是成为一名 在学术医疗中心的独立调查员，研究正常和恶性造血， 照顾血液病患者。 本申请中概述的实验旨在阐明野生型和突变型WT 1在急性胰腺炎中的作用。 骨髓性白血病（AML）进展，目标是为这种疾病创造新的治疗方法。 Wilms tumor 1（WT 1）是一种锌指家族转录因子，在AML细胞中高度表达， 正常造血祖细胞，与促进AML发展的可能作用一致， 导致对WT 1作为治疗靶点的相当大的临床兴趣。奇怪的是，功能丧失 在AML病例的一个子集中也发现了WT 1的突变，这增加了WT 1可能促进或 根据分子背景抑制白血病的发展。我们的实验室最近进行了 研究表明，当与PML-RARA融合共同发生时，WT 1抑制白血病进展， 在小鼠模型中的自我更新，表明在这种情况下，WT 1可以预防或延迟白血病的进展。 为了调和WT 1在AML进展中看似矛盾的作用，我们开发了以下内容 在这个提议中要测试的假设：WT 1表达在造血祖细胞中被触发， 对AML相关驱动突变的防御反应。虽然完全转型的AML已经开发出了 为了克服这种抑制作用，WT 1中随后的功能丧失突变提供了生长优势， 突变亚克隆。与这一假设相一致，我们最近发现WT 1 mRNA被诱导10倍， 已经用几种典型AML相关融合基因转导的CD 34+细胞。在这项提案中， 我们将扩展这些观察，以测试WT 1的过表达或功能缺失是否可以协同 在小鼠和人类系统中与AML相关的突变。