The molecular mechanism of clonal dominance in 5q(del) MDS

5q(del)MDS克隆优势的分子机制

• 批准号: 9312796
• 负责人: Zhijian Qian
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312796
• 关键词: Adenomatous Polyposis Coli; Affect; Binding Sites; Biological Assay; Bone Marrow Cells; CD34 gene; Cell Maintenance; Cells; ChIP-seq; Chromosome Deletion; Chromosome abnormality; Clone Cells; Complex; Data Analyses; Development; Disadvantaged; Disease; Dose; Down-Regulation; Dysmyelopoietic Syndromes; Equilibrium; Event; FOXM1 gene; Family; Functional disorder; Gene Dosage; Gene Expression Profiling; Gene Mutation; Gene Targeting; Genes; Genetic Transcription; Growth; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Human; Immunology; In Vitro; Ineffective Hematopoiesis; Knowledge; Mediating; Microarray Analysis; Molecular; Mus; NR4A1 gene; Nature; Neoplasms; Nuclear Orphan Receptor; Pathogenicity; Pathway interactions; Patients; Play; Role; Sequence Analysis; Signal Pathway; Stem cells; Stress; Testing; Tissues; Transgenic Organisms; Treatment Efficacy; Tumor Suppressor Proteins; aged; base; beta catenin; casein kinase; chromatin modification; chromosome 5q loss; dosage; genome-wide; improved; in vivo; insight; knock-down; loss of function; member; new therapeutic target; novel; self-renewal; transcription factor

Abstract   The molecular mechanism of clonal dominance in del(5q) MDS Myelodysplastic syndrome (MDS) is a clonal stem cell disease, characterized by ineffective hematopoiesis. Sequence analysis provides direct evidence that almost all bone marrow cells are clonally derived in MDS. How the initiating MDS stem cell outcompetes normal hematopoietic stem cells (HSCs) and grows to become dominant in the neoplasm is poorly understood. Explaining how MDS evolves can help us to develop new strategies to improve the therapy of MDS by targeting early molecular events in HSCs in MDS. Deletion of chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities in MDS and therapy-related MDS. We found that the expression of FOXM1, a member of the forkhead family of transcription factors, is reduced to approximately 50-60% of normal expression in CD34+ cells from del(5q) MDS patients. Via loss of function studies, we recently identified a previously unrecognized function of Foxm1 in hematopoietic stem and progenitor cells (HSPCs). In contrast to its known function as a pro-proliferation factor in other tissues, conditional deletion of Foxm1 reduces HSC quiescence, leading to disruption of HSC self-renewal. Our preliminary results revealed that Foxm1 haploinsufficiency promoted HSC exit from quiescence but induced HSC expansion with a competitive repopulation advantage. In addition, we identified orphan nuclear receptors as new down-stream targets of Foxm1 in HSPCs. Orphan nuclear receptors are important regulators of HSC quiescence and self-renewal and are recognized as novel tumor suppressors of hematological malignancies. We found that FOXM1 and its downstream targets were all down-regulated in CD34+ HSPCs from del (5q) MDS patients. Thus, we hypothesize that moderate downregulation of FOXM1-mediated pathways plays a critical role in establishing clonal dominance of MDS stem cell in del(5q) MDS patients and that FOXM1 can be targeted for eliminating MDS stem cells in del(5q) patients. To test this hypothesis, we will 1) determine the pathogenic role of Foxm1 downregulation in the development of MDS; 2) investigate the molecular mechanisms that mediate gene dosage-dependent effects of Foxm1 in regulating HSC quiescence, survival and self-renewal; and 3) determine the upstream pathway that regulates Foxm1 expression in HSPCs. We expect that our studies will uncover a dose-dependent role of Foxm1 as a novel critical regulator of HSC maintenance as well as a novel pathogenic role of Foxm1 in the development of MDS. We expect to identify novel molecular mechanisms that regulate HSC quiescence, survival and self-renewal. These studies will provide mechanistic insights into the acquisition of clonal advantage by MDS stem cells at early stages of del(5q) MDS. Our studies likely will lead to the identification of more effective therapeutic strategies for eliminating disease-propagating cells at early stages of del(5q) MDS by targeting FOXM1.

摘要DEL（5q）MDS克隆主导地位的分子机制 骨髓增生综合征（MDS）是一种克隆干细胞疾病，其特征是 无效的造血。序列分析提供了几乎所有骨头的直接证据 骨髓细胞在MDS中衍生在克隆中。启动的MDS干细胞如何正常 造血干细胞（HSC）并成长为在肿瘤中占主导地位 理解。解释MDS的演变如何帮助我们制定新的策略来改善 通过靶向MDS中HSC的早期分子事件的MDS治疗。染色体的缺失 5q [del（5q）]是MDS中最常见的细胞遗传学异常之一和与治疗有关 MDS。我们发现Foxm1的表达是叉子转录家族的成员 从DEL中的CD34+细胞中，因子降低至正常表达的约50-60％（5Q） MDS患者。通过丧失功能研究，我们最近确定了先前未知的 FOXM1在造血干和祖细胞（HSPC）中的功能。与已知的相反 在其他组织中充当促分化因子，有条件的FOXM1缺失可减少 HSC静止，导致HSC自我更新的破坏。我们的初步结果显示 FOXM1单倍弥补促进了HSC从静止的出口，但诱导了HSC膨胀 具有竞争性的重新流行优势。此外，我们确定了孤儿核接收器 作为HSPC中FOXM1的新下游目标。孤儿核接收器很重要 HSC静止和自我更新的调节剂，被认为是新型肿瘤补充剂 血液学恶性肿瘤。我们发现FOXM1及其下游目标都是 来自DEL（5Q）MDS患者的CD34+ HSPC中下调。那我们假设 FOXM1介导的途径的适度下调在建立中起着至关重要的作用 DEL（5Q）MDS患者中MDS干细胞的克隆优势，并且可以将FOXM1靶向 用于消除DEL（5Q）患者中的MDS干细胞。为了检验这一假设，我们将确定 FOXM1下调在MDS发展中的致病作用； 2）调查 介导FOXM1基因剂量依赖性作用的分子机制 HSC静止，生存和自我更新； 3）确定上游途径 调节HSPC中FOXM1的表达。 我们希望我们的研究将发现FoxM1作为一种新颖的剂量依赖性作用 HSC维护的关键调节剂以及FOXM1的新型致病作用 MDS的发展。我们期望确定调节HSC的新型分子机制 静止，生存和自我更新。这些研究将提供有关机械的见解 MDS干细胞在DEL（5Q）MDS的早期阶段获得克隆优势。我们的研究 可能会导致确定消除更有效的治疗策略 通过靶向FOXM1，在DEL（5Q）MD的早期阶段促进疾病的细胞。