The Role of MEIS1 in Hematopoiesis and Hematopoietic Transformation

MEIS1 在造血和造血转化中的作用

基本信息

批准号：
8371424
负责人：
Ashish Kumar
金额：
$ 38.25万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8371424
关键词：
11q23 Address Adult Affect Binding Proteins Biological Biology Bone Marrow Cell Cycle Cell Cycle Regulation Cell Maintenance Cell Proliferation Cells Constitutional DNA Sequence Rearrangement Data Development Disease Embryo Experimental Models Gene Expression Genes Genetic Genetic Models Goals Growth HOXA9 gene Hematopoiesis Hematopoietic Hemorrhage Human Hypoxia Infant Knock-in Mouse Knock-out Knockout Mice Knowledge MEIS1 gene MLL gene MLL-AF9 Maintenance Mediating Methodology Modeling Molecular Mus Outcome Pathogenesis Pathway interactions Patients Physiological Process Proteins Regulation Research Role Stem cells Testing Therapeutic Treatment outcome Work alpha-Thalassemia base cofactor effective therapy fusion gene improved in vivo innovation leukemia mouse model new therapeutic target novel protein protein interaction reconstitution response small hairpin RNA therapeutic target therapy development

项目摘要

DESCRIPTION (provided by applicant): Majority of infant leukemias involve rearrangements in the MLL gene and are most often fatal. These leukemias are characterized by high expression of MEIS1 but the biologic roles of MEIS1 in leukemia are not defined. The long term goal is to improve the outcome for MLL-fusion gene leukemia by developing newer more effective therapies. The objective of this application is to determine the role of MEIS1 in MLL-fusion gene leukemia and in hematopoiesis with the aim of understanding the therapeutic utility and window of targeting MEIS1 as a therapy. The experimental model studied will be inducible MEIS1 knock-out mice and MLL-AF9 knock-in mice. The first specific aim is to determine the requirement of MEIS1 in the maintenance of MLL-AF9 leukemia and of normal hematopoiesis. The central hypothesis is that MEIS1 is critical for MLL-AF9 leukemia but dispensable for normal hematopoiesis. The experimental strategy will be inducible deletion of MEIS1 in the bone marrow of MLL-AF9 and otherwise normal mice. The MEIS1-deleted and MEIS1-replete cells will be compared in their ability to maintain and reconstitute normal and leukemic hematopoiesis. The second specific aim is to identify the molecular functions of MEIS1. We have generated preliminary data from shRNA knockdown and genetic deletion studies. The central hypothesis is that MEIS1 is required for the regulation of the cell cycle and of the hypoxia-response pathway. The role of the hypoxia-response regulator - Hif-1a and its regulation by MEIS1 will be determined using the inducible MEIS1 knockout models of leukemia. Finally, the role of MEIS1-binding proteins such PBX1 will also be studied in these experimental models. The proposed studies are innovative since they address the role of MEIS1 in established leukemia and in hematopoiesis using robust genetic models and address the molecular mechanisms engaged by MEIS1 in physiologic experimental models. The proposed research is significant because it will fundamentally enhance the existing knowledge of hematopoiesis and of MLL-fusion gene leukemia while also identifying targets for novel therapies. PUBLIC HEALTH RELEVANCE: Effective therapies for MLL-leukemias are limited by the lack of knowledge of the underlying biology of the disease process. The results of the proposed research will help the development of effective therapies for this dreadful disease.

描述（由申请人提供）：大多数婴儿白血病涉及MLL基因中的重排，并且通常是致命的。这些白血病的特征是Meis1的高表达，但Meis1在白血病中的生物学作用尚未定义。长期目标是通过开发更新的更有效的疗法来改善MLL融合基因白血病的结果。该应用的目的是确定MEIS1在MLL融合基因白血病和造血中的作用，目的是理解靶向MEIS1作为治疗的治疗效用和窗口。研究的实验模型将是可诱导的Meis1敲除小鼠和MLL-AF9敲门小鼠。第一个具体目的是确定MEIS1在维持MLL-AF9白血病和正常造血的需求。中心假设是MEIS1对于MLL-AF9白血病至关重要，但对于正常造血至关重要。实验策略将在MLL-AF9和其他正常小鼠的骨髓中诱导MEIS1诱导。将比较Meis1删除的细胞和MEIS1-取代细胞的维持和重建正常和白血病造血的能力。第二个具体目的是识别MEIS1的分子功能。我们已经从SHRNA敲低和遗传缺失研究中产生了初步数据。中心假设是Meis1是细胞周期和缺氧反应途径的调节所必需的。低氧反应调节剂-HIF-1A及其对MEIS1的调控的作用将使用白血病的诱导MEIS1敲除模型确定。最后，在这些实验模型中，还将研究Meis1结合蛋白的作用。拟议的研究具有创新性，因为它们使用强大的遗传模型解决了MEIS1在已建立的白血病和造血中的作用，并解决了MEIS1在生理实验模型中参与的分子机制。拟议的研究之所以重要，是因为它从根本上可以增强造血和MLL融合基因白血病的现有知识，同时还确定了新型疗法的靶标。公共卫生相关性：MLL- leukemias的有效疗法受到对疾病过程的潜在生物学知识的了解的限制。拟议的研究结果将有助于开发这种可怕疾病的有效疗法。