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

5q(del)MDS克隆优势的分子机制

基本信息

批准号：
9795448
负责人：
Zhijian Qian
金额：
$ 34.31万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9795448
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 Genes Genetic Transcription Growth Hematologic Neoplasms Hematology 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 Xenograft procedure aged base beta catenin casein kinase chromatin modification chromosome 5q loss dosage genome-wide hematopoietic stem cell expansion hematopoietic stem cell quiescence hematopoietic stem cell self-renewal improved in vivo insight knock-down loss of function member new therapeutic target novel self-renewal transcription factor

项目摘要

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 克隆优势的分子机制骨髓增生异常综合征（MDS）是一种克隆干细胞疾病，其特征为序列分析提供了几乎所有骨的无效造血的直接证据。 MDS 中的骨髓细胞是克隆衍生的。起始 MDS 干细胞如何在竞争中胜过正常细胞。造血干细胞（HSC）在肿瘤中生长并成为主导细胞的能力很差解释 MDS 如何演变可以帮助我们制定新的策略来改进。通过针对MDS中HSC的早期分子事件来治疗MDS。 5q [del(5q)] 是 MDS 和治疗相关的最常见的细胞遗传学异常之一 MDS。我们发现FOXM1（转录叉头家族的成员）的表达 CD34+ 细胞中 del(5q) 的表达量减少至正常表达的约 50-60% 通过功能丧失研究，我们最近发现了一种以前未被识别的 MDS 患者。 Foxm1 在造血干细胞和祖细胞 (HSPC) 中的功能与其已知的功能相反。作为其他组织中的促增殖因子，条件性删除 Foxm1 可减少 HSC 静止，导致 HSC 自我更新中断。我们的初步结果显示。 Foxm1 单倍体不足促进 HSC 退出静止状态，但诱导 HSC 扩增此外，我们还发现了核孤儿受体。作为 HSPC 中 Foxm1 的新下游靶点非常重要。 HSC 静止和自我更新的调节因子，被认为是新型肿瘤抑制因子我们发现FOXM1及其下游靶标都是血液系统恶性肿瘤的。 del (5q) MDS 患者的 CD34+ HSPC 下调，因此，我们对此感到困惑。 FOXM1 介导的通路的中度下调在建立 del(5q) MDS 患者中 MDS 干细胞的克隆优势，并且可以靶向 FOXM1 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 发展中的致病作用 2) 研究介导 Foxm1 基因剂量依赖性调节作用的分子机制 HSC 静止、存活和自我更新；3) 确定上游途径调节 HSPC 中 Foxm1 的表达。我们期望我们的研究将揭示 Foxm1 作为一种新型药物的剂量依赖性作用 Foxm1 是 HSC 维持的关键调节因子以及新的致病作用我们期望找到调节 HSC 的新分子机制。这些研究将为我们提供关于静止、生存和自我更新的机制见解。 MDS 干细胞在 del(5q) MDS 的早期阶段获得克隆优势。可能会导致确定更有效的治疗策略来消除通过靶向 FOXM1，在 del(5q) MDS 早期阶段抑制疾病传播细胞。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TFII-I/Gtf2i and Erythro-Megakaryopoiesis.

DOI：
10.3389/fphys.2020.590180
发表时间：
2020
期刊：
Frontiers in physiology
影响因子：
4
作者：
Gurumurthy A;Wu Q;Nar R;Paulsen K;Trumbull A;Fishman RC;Brand M;Strouboulis J;Qian Z;Bungert J
通讯作者：
Bungert J

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