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(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 造血功能无效。序列分析提供了直接证据表明几乎所有的骨骼 MDS 中的骨髓细胞是克隆衍生的。起始MDS干细胞如何战胜正常细胞 造血干细胞（HSC）在肿瘤中生长并成为主导细胞的能力很差 明白了。解释 MDS 如何演变可以帮助我们制定新策略来改善 通过针对 MDS 中 HSC 的早期分子事件来治疗 MDS。染色体缺失 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。我们发现转录叉头家族成员 FOXM1 的表达 CD34+ 细胞中 del(5q) 的表达量减少至正常表达的约 50-60% 骨髓增生异常综合征患者。通过功能丧失研究，我们最近发现了一个以前未被识别的 Foxm1 在造血干细胞和祖细胞 (HSPC) 中的功能。与它已知的相比 作为其他组织中的促增殖因子，条件性删除 Foxm1 会减少 HSC 静止，导致 HSC 自我更新中断。我们的初步结果揭晓 Foxm1单倍体不足促进HSC退出静止状态，但诱导HSC扩张 具有人口再竞争优势。此外，我们还鉴定了孤儿核受体 作为 HSPC 中 Foxm1 的新下游目标。孤儿核受体很重要 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 血液系统恶性肿瘤。我们发现FOXM1及其下游靶标均 del (5q) MDS 患者的 CD34+ HSPC 中下调。因此，我们假设 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。 为了检验这个假设，我们将 1) 确定 Foxm1 下调在 MDS 发展中的致病作用； 2）调查 介导 Foxm1 基因剂量依赖性调节作用的分子机制 HSC的静止、生存和自我更新； 3) 确定上游路径 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 MDS 的发展。我们期望找到调节 HSC 的新分子机制 静止、生存和自我更新。这些研究将提供有关机制的见解 MDS 干细胞在 del(5q) MDS 早期阶段获得克隆优势。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

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