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.

Del(5q)MDS克隆显性的分子机制 骨髓增生异常综合征(MDS)是一种克隆性干细胞疾病，其特征是 无效的造血。序列分析提供了直接证据，几乎所有的骨骼 MDS患者的骨髓细胞是克隆性来源的。启动MDS干细胞如何在竞争中脱颖而出 造血干细胞(HSCs)在肿瘤中生长并成为主导细胞的情况较差。 明白了。解释MDS是如何发展的可以帮助我们开发新的战略来改进 靶向MDS患者造血干细胞早期分子事件治疗MDS染色体缺失 5q[del(5q)]是MDS最常见的细胞遗传学异常之一，与治疗相关 MDS。我们发现Forkhead转录家族成员FOXM1的表达 因子，从del(5q)降低到CD34+细胞正常表达的大约50%-60% MDS患者。通过功能丧失研究，我们最近发现了一种以前未被识别的 FOXM1在造血干/祖细胞中的作用与它已知的相反 在其他组织中作为促增殖因子发挥作用，条件删除FOXM1会减少 HSC静止，导致HSC自我更新中断。我们的初步结果显示 FOXM1单倍体缺陷促进HSC退出静止但诱导HSC扩张 具有竞争性的再繁殖优势。此外，我们还发现了孤儿核受体 作为HSPC FOXM1的新下游目标。孤儿核受体很重要 肝星状细胞静止和自我更新的调节因子，被认为是新的肿瘤抑制因子 血液系统恶性疾病。我们发现FOXM1及其下游目标都是 Del(5q)MDS患者CD34+HSPC表达下调。因此，我们假设 适度下调FOXM1介导的通路在建立 Del(5q)MDS患者MDS干细胞克隆优势及FOXM1可靶向性研究 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1)确定 FOXM1下调在MDS发生发展中的致病作用；2)研究 FOXM1调节基因剂量依赖效应的分子机制 HSC的静止、存活和自我更新；3)决定上游通路， 调节HSPC中FOXM1的表达。 我们预计，我们的研究将揭示FOXM1作为一种新的 HSC维持的关键调节因子以及FOXM1在HSC维持中的新致病作用 MDS的发展。我们希望确定调节HSC的新的分子机制 宁静、生存、自我更新。这些研究将提供对 MDS干细胞在del(5q)MDS早期获得克隆优势。我们的研究 可能会导致确定更有效的治疗策略，以消除 通过靶向FOXM1在del(5q)MDS的早期阶段传播疾病的细胞。