Regulation of hematopoiesis by CUX1

CUX1 对造血的调节

• 批准号: 10202705
• 负责人: Megan McNerney
• 金额: $ 39.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202705
• 关键词: Acute leukemia; Address; Anemia; Biological Assay; Biology; Blood; Blood Cells; Blood Platelets; Cell Cycle; Cell Cycle Regulation; Cells; Chromosome 7; Chromosome Deletion; Chromosome abnormality; Clinical; Cyclins; Defect; Development; Disease; Down-Regulation; Drosophila genus; Dysmyelopoietic Syndromes; Dysplasia; Erythroblasts; Erythrocytes; Erythroid; Erythropoiesis; Future; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Goals; Health Care Costs; Hematopoiesis; Hematopoietic stem cells; Human; In Vitro; Knowledge; Laboratories; Leukocytes; Megakaryocytes; Molecular; Morbidity - disease rate; Mus; Mutation; Myelogenous; Myeloproliferative disease; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Prevalence; Production; Prognosis; Public Health; Quality of life; Recurrence; Regulation; Reporting; Research Personnel; Risk; Role; Signal Transduction; Transcriptional Activation; Transcriptional Regulation; United States; Work; chromosome 7 loss; chromosome 7q loss; cytopenia; design; effectiveness evaluation; erythroid differentiation; exhaustion; functional genomics; granulocyte; homeodomain; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; kinase inhibitor; knock-down; mortality; mouse model; myelodysplastic anemia; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; preclinical study; prevent; progenitor; self-renewal; stem cell function; stem cell homeostasis; stem cell proliferation; transcription factor; transcriptome

PROJECT SUMMARY Myelodysplastic syndromes (MDS) are disorders of hematopoietic stem and progenitor cells (HSPCs) that results in cytopenias, however, the genetic causes of this dysfunctional hematopoiesis remain unclear. Almost all patients suffer anemia, a major cause of morbidity, mortality, and health care costs. Deletion of part or all of chromosome 7 [-7/del(7q)] is a common cytogenetic abnormality in MDS and carries a poor prognosis. We identified CUX1, a homeodomain-containing transcription factor encoded on 7q, to be frequently inactivated in myeloid diseases. We reported that CUX1 has highly conserved regulatory functions in both human and Drosophila blood cells. CUX1 inactivating mutations have since been reported in MDS and are independently associated with a poor prognosis. We have now generated an innovative Cux1 knockdown mouse model. Cux1-knockdown mice develop a spontaneous myeloproliferative disorder with many features of human MDS, including megakaryocyte, granulocyte, and erythroid dysplasia, and a fatal anemia. Preliminary studies indicate that Cux1 knockdown impacts multiple stages of hematopoiesis, disrupting early HSPC functions as well as blocking late stages of erythroid development. A major knowledge gap, which this proposal is designed to address, is the mechanism by which CUX1 regulates normal hematopoiesis. The overall objective is to determine the transcriptional role for CUX1 in normal HSPCs and erythroid progenitors and the pathways downstream of CUX1 haploinsufficiency that block erythroid differentiation. Aim 1: Hypothesis – CUX1 is a transcriptional regulator of HSPC homeostasis conserved in mice and humans. We will take advantage of our novel mouse model for in vivo analyses of Cux1 regulation of HSPC quiescence, proliferation, and differentiation. We will perform complementary studies with primary human HSPCs to establish the translational relevance of this work. We will capitalize on leading-edge functional genomics approaches to identify CUX1 genomic targets in human HSPCs. Aim 2: Hypothesis – CUX1 promotes erythroblast cell cycle exit necessary for terminal differentiation by repressing PI3K signaling. We will identify the specific developmental stage of erythropoiesis disrupted by Cux1 knockdown in mice. We will determine the conserved role for CUX1 in human red cell development, and the pathways induced by CUX1 deficiency that disrupt erythropoiesis. Our functional and genomic analyses of primary human HSCs will dovetail with in vivo assays to elucidate the critical role for CUX1 transcriptional regulation of normal erythropoiesis. This work will have a positive impact on the fields of HSC and erythroid biology by identifying the molecular mechanism by which CUX1 regulates normal HSC functions and the pathogenesis of CUX1-deficiency in disease states. Our studies will reveal novel therapeutic targets for treating anemia in MDS patients and a murine model of MDS for preclinical studies.

项目摘要 骨髓增生异常综合征（MDS）是造血干细胞和祖细胞（HSPC）的病症， 然而，这种造血功能障碍的遗传原因仍不清楚。几乎 所有患者都患有贫血症，这是发病率、死亡率和卫生保健费用的主要原因。删除部分或全部 7号染色体[-7/del（7 q）]是MDS中常见的细胞遗传学异常，并且具有不良预后。我们 确定了CUX 1，一种在7 q上编码的含有同源结构域的转录因子，在 骨髓疾病我们报道了CUX 1在人和哺乳动物中具有高度保守的调节功能， 果蝇血细胞CUX 1失活突变已在MDS中报道，并且与MDS的发病无关。 与预后不良有关。我们现在已经产生了一个创新的Cux 1敲除小鼠模型。 Cux 1基因敲除小鼠发生具有许多人MDS特征的自发性骨髓增生性疾病， 包括巨核细胞、粒细胞和红细胞发育不良以及致命性贫血。初步研究 表明Cux 1敲低影响造血的多个阶段，破坏早期HSPC功能， 以及阻断红细胞发育的晚期阶段。一个主要的知识差距，这一建议的目的是 要解决的是CUX 1调节正常造血的机制。总体目标是 确定CUX 1在正常HSPC和红系祖细胞中的转录作用以及 CUX 1单倍不足的下游，阻断红细胞分化。目标1：假设-CUX 1是一个 在小鼠和人类中保守的HSPC稳态的转录调节因子。我们将利用我们的 用于体内分析Cux 1调节HSPC静止、增殖和凋亡的新型小鼠模型 分化我们将对原代人HSPC进行补充研究，以建立 翻译的相关性。我们将利用前沿的功能基因组学方法， 鉴定人HSPC中的CUX 1基因组靶标。目的2：假设-CUX 1促进成红细胞细胞周期 通过抑制PI 3 K信号传导，退出终末分化所必需的。我们将确定具体 在小鼠中通过Cux 1敲低破坏红细胞生成的发育阶段。康贝特人将以 CUX 1在人类红细胞发育中的保守作用，以及由CUX 1缺陷诱导的途径， 破坏红细胞生成我们对原代人HSC的功能和基因组分析将与体内研究相吻合。 本发明还涉及用于阐明正常红细胞生成的CUX 1转录调节的关键作用的测定。这项工作将 对HSC和红细胞生物学领域产生积极影响， CUX 1调节正常HSC功能和疾病状态下CUX 1缺乏的发病机制。我们 研究将揭示治疗MDS患者和MDS小鼠模型贫血的新治疗靶点 用于临床前研究。