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: 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
• 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

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（5 q）MDS克隆优势的分子机制 骨髓增生异常综合征（MDS）是一种克隆性干细胞疾病，其特征在于： 无效造血序列分析提供了直接证据表明几乎所有的骨骼 骨髓细胞在MDS中克隆衍生。如何启动MDS干细胞胜过正常 造血干细胞（HSC）和生长成为占主导地位的肿瘤是差 明白解释MDS如何演变可以帮助我们制定新的战略，以改善 通过靶向MDS中HSC中的早期分子事件来治疗MDS。号染色体缺失 5 q [del（5 q）]是MDS中最常见的细胞遗传学异常之一， MDS我们发现FOXM 1的表达，FOXM 1是转录叉头家族的成员， 在来自del（5 q）的CD 34+细胞中， MDS患者。通过功能丧失的研究，我们最近发现了一种以前未被认识到的 Foxm 1在造血干细胞和祖细胞（HSPC）中的功能。与其已知的 在其他组织中作为促增殖因子发挥作用，Foxm 1的条件性缺失减少了 HSC静止，导致HSC自我更新中断。我们的初步结果显示 Foxm 1单倍不足促进HSC从静止状态退出，但诱导HSC扩增， 有竞争力的繁殖优势。此外，我们还鉴定了孤儿核受体， 作为HSPC中Foxm 1的新下游靶点。孤儿核受体很重要 HSC静止和自我更新的调节剂，被认为是新的肿瘤抑制剂 血液系统恶性肿瘤我们发现FOXM 1及其下游靶点都是 在来自del（5 q）MDS患者的CD 34 + HSPC中下调。因此，我们假设， FOXM 1介导的通路的适度下调在建立一种新的免疫应答机制中起着关键作用。 在del（5 q）MDS患者中MDS干细胞的克隆优势以及FOXM 1可以被靶向 为了验证这一假设，我们将1）确定 Foxm 1下调在MDS发展中的致病作用; 2）研究Foxm 1下调在MDS发病中的作用。 调节Foxm 1基因剂量依赖性作用的分子机制 HSC静止、存活和自我更新;以及3）确定 调节HSPC中Foxm 1的表达。 我们希望我们的研究将揭示Foxm 1作为一种新的剂量依赖性作用。 HSC维持的关键调节因子以及Foxm 1在HSC损伤中的新致病作用。 MDS的发展。我们希望能发现新的调控HSC的分子机制 静止、生存和自我更新。这些研究将提供机械的见解， 在del（5 q）MDS的早期阶段通过MDS干细胞获得克隆优势。我们的研究 可能会导致确定更有效的治疗策略，消除 在del（5 q）MDS的早期阶段通过靶向FOXM 1的疾病传播细胞。

项目成果

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

Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response.

• DOI: 10.1093/nar/gkab415
• 发表时间: 2021-06-04
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Yu F;Wei J;Cui X;Yu C;Ni W;Bungert J;Wu L;He C;Qian Z
• 通讯作者: Qian Z