Regulation of hematopoietic stem cell and progenitor cell proliferation by Runx1

描述(申请人提供)：这项建议的目的是阐明RUNX1在造血干细胞和祖细胞中的缺失改变它们的功能，并促进骨髓增生异常综合征(MDS)和急性髓系白血病(AML)的发展的机制。RUNX1的失活突变在分化最低的M0亚型的AML患者和MDS患者中发现的比例很高。MDS是一组血液疾病的集合，其特征是一个或多个血细胞系的产生效率低下，目前除了骨髓移植外，还没有治愈的方法。在小鼠中RUNX1的丢失似乎概括了MDS的早期阶段，因此是研究RUNX1功能受损如何促进这种疾病发展的模型。我们发现RUNX1的缺失会导致造血干细胞和多能祖细胞更频繁地增殖，大约2000个基因和40个microRNAs的表达在这些人群中发生了变化。在这里，我们建议描述由RUNX1缺陷引起的造血干细胞和祖细胞的缺陷。我们将研究在RUNX1缺陷的HSCs中表达异常的基因是否与这些缺陷有关。我们将确定用一种表达不足的细胞因子受体激动剂治疗小鼠是否能改善植入性。最后，我们将评估几个microRNAs对与RUNX1缺乏相关的植入缺陷的贡献，以及它们导致MDS的能力。

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the mechanisms by which loss of Runx1 in hematopoietic stem and progenitor cells alters their function, and contributes to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Inactivating mutations in RUNX1 are found in a high percentage of patients with AML of the least differentiated M0 subtype, and in MDS. MDS is a collection of blood disorders characterized by the inefficient production of one or more blood cell lineages, for which there is currently no cure aside from bone marrow transplantation. Loss of Runx1 in mice appears to recapitulate early stages of MDS, and is therefore a model for studying how impaired Runx1 function contributes to the development of this disease. We showed that loss of Runx1 causes hematopoietic stem cells and multipotent progenitors to proliferate more frequently, and that the expression of approximately 2000 genes and 40 microRNAs is altered in these populations. Here we propose to characterize the defects in HSCs and progenitors caused by Runx1 deficiency. We will examine whether genes whose expression is dysregulated in Runx1 deficient HSCs contribute to these defects. We will determine if treatment of mice with an agonist of a cytokine receptor that is under-expressed improves engraftment. Finally we will assess the contribution of several microRNAs to the engraftment defects associated with Runx1 deficiency, and their ability to cause MDS.