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：探讨del(5q) MDS克隆显性的分子机制

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