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）：本提案的总体目标是确定 IEX-1（立即早期反应基因 X-1）作为早期诊断骨髓增生异常综合征 (MDS) 或其进展为急性髓系细胞的生物标志物的潜力白血病（AML）。 MDS 是造血干细胞 (HSC) 的一种克隆性疾病，可能是由于控制 HSC 分化、自我更新或增殖的基因突变积累所致。 MDS 患者 HSC 中异常高频率的遗传改变可能部分归因于活性氧 (ROS) 产生的增加，从而导致 DNA 突变，进而导致额外的基因组变化和 ROS 形成。 IEX-1 通过靶向降解线粒体 FoF1-ATP 合酶 (IF1) 抑制剂，参与调节线粒体中 ROS 生成和氧化磷酸化之间的平衡。 IEX-1 的过度表达降低了 IF1 的表达水平，同时减少了 ROS 的产生，从而保护细胞免受线粒体依赖性细胞凋亡。相反，IEX-1的无效突变稳定了IF1的表达并增加了细胞凋亡的易感性。与 IEX-1 在 HSC 存活和分化中的作用一致，IEX-1 缺陷的 HSC 表现出高凋亡和增殖率，但其生成量减少。此外，最近的多项研究表明，一半以上的MDS患者IEX-1表达失调，并且这种失调与疾病进展和患者CD34+干细胞的凋亡水平相关。基于这些观察结果，我们假设 IEX-1 表达的失调对 MDS 的发展及其向 AML 的进展有显着贡献。我们将通过长期竞争性再增殖测定来检验这一假设，以确定 IEX-1 是否或如何通过自主或外在方式促进 MDS 发展。然后，重组小鼠将接受抗氧化剂治疗，以恢复造血干细胞的自我更新能力。在目标 2 中，我们将 IEX-1 敲除 (KO) 小鼠暴露于提供“第二次打击”的放疗或化疗，使它们更容易受到放疗或化疗诱导的 DNA 突变的影响，从而导致 MDS/AML 的发展。 IEX-1 KO小鼠治疗后对MDS/AML的易感性增加表明IEX-1是导致HSC基因组不稳定的“多重打击”之一，因此可以用作MDS/AML预后的生物标志物。骨髓疾病。该研究还可能为疾病发展机制提供新的见解，并有助于制定新的预防策略。