IEX-1 as a potential biomarker for early detection of myelodysplastic syndromes

IEX-1 作为早期检测骨髓增生异常综合征的潜在生物标志物

基本信息

批准号：
8311631
负责人：
Mei X Wu
金额：
$ 17.24万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311631
关键词：
Acute Myelocytic Leukemia Address Aftercare Antioxidants Apoptosis Automobile Driving Biological Assay Biological Markers Bone Marrow Stem Cell CD34 gene Cell Cycle Arrest Cell membrane Cells Chromosomal Loss Cytotoxic Chemotherapy DNA Damage Development Disease Disease Progression Dysmyelopoietic Syndromes Dysplasia Early Diagnosis Elderly Epigenetic Process Equilibrium Exhibits Frequencies Gene Mutation Generations Genes Genomic Instability Genomics Growth Hematopoietic Neoplasms Hematopoietic stem cells Homeostasis Induced Mutation Ineffective Hematopoiesis Investigation Knock-out Knockout Mice Lead Lesion Mitochondria Modification Mus Mutation Myelogenous NADPH Oxidase Oxidative Phosphorylation Patients Play Point Mutation Predisposition Production Radiation Reactive Oxygen Species Recurrence Regulation Respiratory Chain Role Secondary to Site Stem cells Testing Wild Type Mouse base chemotherapy cytopenia inhibitor/antagonist insight mitochondrial dysfunction novel strategies null mutation outcome forecast peripheral blood prevent reconstitution regenerative self-renewal

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine a potential of IEX-1 (Immediate Early responsive gene X-1) as a biomarker for the early diagnosis of myelodysplastic syndromes (MDS) or its progression to acute myeloid leukemia (AML). MDS is a clonal disorder of hematopoietic stem cells (HSCs) presumably resulting from the accumulation of mutations in genes that control the differentiation, self-renewal, or proliferation of HSCs. An unusual high frequency of genetic alterations in HSCs in MDS patients may be ascribed in part to increased production of reactive oxygen species (ROS) that causes DNA mutations, which could in turn lead to acquisition of additional genomic changes and ROS formation. IEX-1 takes part in regulating a balance between ROS generation and oxidative phosphorylation in mitochondria by targeting the inhibitor of mitochondrial FoF1-ATP synthase (IF1) to degradation. Over-expression of IEX-1 reduced the level of IF1 expression, concomitant with diminished ROS production, protecting cells from mitochondrion-dependent apoptosis. On the contrary, null mutation of IEX-1 stabilized IF1 expression and increased the susceptibility of cells to apoptosis. In accordance with a role of IEX-1 in the survival and differentiation of HSCs, IEX-1 deficient HSCs exhibited a high rate of apoptosis and proliferation but a decrease in their generation. Moreover, several studies recently showed that IEX-1 expression was deregulated in more than half of patients with MDS and the deregulation was correlated with the progression of the disease and the apoptosis level in CD34+ stem cells in the patients. Based on these observations, we hypothesize that deregulation of IEX-1 expression contributes significantly to the development of MDS and its progression to AML. We will test this hypothesis by long term competitive repopulation assays so as to determine whether or how IEX-1 contributes to MDS development via an autonomous or extrinsic fashion. The reconstituted mice will be then treated with anti-oxidant to restore the self-renewal capacity of HSCs. In aim 2, we will expose IEX-1 knockout (KO) mice to radiation or chemotherapy that offers a "second hit", rendering them more susceptible to radiation- or chemotherapy-induced DNA mutations and thus MDS/AML development. An increase in the susceptibility of IEX-1 KO mice to MDS/AML after the treatment will suggest that IEX-1 is one of the "multiple hits" causing the genomic instability in HSCs and can be thus used as a biomarker for the prognosis of myeloid disorders. The study may also provide new insights into the mechanism for the disease development and help to develop novel strategies to prevent it.

描述（由申请人提供）：该提案的总体目的是确定IEX-1（立即反应性基因X-1）作为早期诊断骨髓增生综合征（MDS）的生物标志物或其发展为急性髓样白血病（AML）的生物标志物。 MDS是造血干细胞（HSC）的克隆疾病，可能是由于控制HSC的分化，自我更新或增殖的基因中的突变而产生的。 MDS患者中HSC的遗传改变的异常高频率可能部分归因于导致DNA突变的活性氧（ROS）的产生增加，这又可能导致获得其他基因组变化和ROS形成。 IEX-1通过靶向线粒体FOF1-ATP合酶（IF1）的抑制剂来调节线粒体中ROS产生和氧化磷酸化之间的平衡。 IEX-1的过表达降低了IF1表达的水平，与ROS产生减少，保护细胞免受线粒体依赖性凋亡。相反，IEX-1的无效突变使IF1表达稳定，并增加了细胞对凋亡的敏感性。根据IEX-1在HSC的生存和分化中的作用，IEX-1缺乏的HSC表现出高凋亡和增殖率很高，但其一代降低。此外，最近的几项研究表明，在超过一半的MDS患者中，IEX-1表达在失控中被放松，并且与疾病的进展和CD34+干细胞中疾病的进展和凋亡水平相关。基于这些观察结果，我们假设对IEX-1表达的放松管制对MD的发展及其向AML的发展产生了重大贡献。我们将通过长期竞争性重生测定法检验这一假设，以确定IEX-1是否通过自主或外部方式对MDS开发贡献。然后，将用抗氧化剂处理重构的小鼠，以恢复HSC的自我更新能力。在AIM 2中，我们将使IEX-1基因敲除（KO）小鼠进行放射或化学疗法，以提供“第二次命中”，从而使它们更容易受到放疗或化学疗法诱导的DNA突变，从而更容易受到MDS/AML的发育。治疗后，IEX-1 KO小鼠对MDS/AML的敏感性的提高将表明IEX-1是引起HSC中基因组不稳定性的“多重命中”之一，因此可以用作髓样疾病预后的生物标志物。这项研究还可以提供有关疾病发展机制的新见解，并有助于制定新的策略来预防疾病。