Regulation of RUNX1 Multiprotein Complex Formation during Hematopoiesis

造血过程中 RUNX1 多蛋白复合物形成的调控

• 批准号: 8632270
• 负责人: ALAN B. CANTOR
• 金额: $ 25.17万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632270
• 关键词: Affect; Alleles; Cell Maintenance; Cell Maturation; Cell Ontogeny; ChIP-seq; Chromatin Remodeling Factor; Clinical; Co-Immunoprecipitations; Data; Development; Disease; Dominant-Negative Mutation; Dysmyelopoietic Syndromes; Enzymes; Epigenetic Process; Equilibrium; Event; Family; Fusion Oncogene Proteins; Gel Chromatography; Gene Expression; Generations; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Knowledge; Laboratories; Link; Lymphocyte; MEKs; Maintenance; Malignant - descriptor; Mediating; Megakaryocytes; Mitogen-Activated Protein Kinases; Molecular; Mono-S; Multiprotein Complexes; Mutation; Myeloproliferative disease; Outcome; Output; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Play; Predisposition; Proteins; Proteomics; RUNX1 gene; Recurrence; Regulation; Research; Residual state; Role; Signal Pathway; Signal Transduction; Stem Cell Development; Stem cells; T-Lymphocyte; Testing; Translating; Tyrosine Phosphorylation; Validation; Work; base; high risk; improved; inhibitor/antagonist; leukemia; leukemogenesis; loss of function mutation; mouse model; novel; outcome forecast; prevent; progenitor; protein protein interaction; public health relevance; research study; small molecule; src-Family Kinases; stem; therapeutic target; transcription factor; treatment strategy

Summary The transcription factor RUNX1 plays essential roles in definitive hematopoietic stem cell (HSC) ontogeny, HSC maintenance, megakaryocyte (Mk) maturation, and lymphocyte differentiation. RUNX1 deficiency causes an imbalance of HSC and progenitor cells, and is an early initiating step in up to 30% of all human leukemias. RUNX1 is also a recurrent target of heterozygous inactivating mutations in high-risk myelodysplastic syndrome (MDS). Despite RUNX1's central role in normal and malignant human hematopoiesis, its regulatory mechanisms remain incompletely understood. This gap in knowledge has impeded efforts to exploit RUNX1 as a therapeutic target. The long-term goal of our research is to elucidate these mechanisms and translate them into new treatment strategies. Our prior work and that of others in the field indicates that RUNX1 assembles into large dynamic multiprotein complexes that modulate its activity. These interactions involve other transcription factors, epigenetic regulators, and signaling enzymes. We hypothesize that these interactions are modulated by cell signaling pathways and that pharmacologic manipulation of these pathways can be used to enhance residual RUNX1 activity in disorders associated with partial RUNX1 deficiency. This is based on our preliminary studies demonstrating steady-state inhibition of RUNX1 activity by src-family kinases (SFKs), and synergistic RUNX1:Ets transcription factor interactions involving a region targeted by MEK/ERK-mediated phosphorylation. The following aims have been developed to test our central hypothesis: (1) identify changes in RUNX1 multiprotein complex formation that occur during cellular maturation and correlate them with RUNX1 activity; (2) determine how SFK and ERK signaling pathways modulate RUNX1 interactions with chromatin remodeling complexes/transcription factors and how they affect RUNX1 target gene expression; (3) Explore whether pharmacologic enhancement of residual RUNX1 activity can alleviate the HSC/progenitor cell imbalance observed with partial RUNX1 deficiency and impact leukemogenesis in mouse models of RUNX1 dominant negative fusion molecules. The results of these studies should fill in important gaps in knowledge regarding normal RUNX1 regulatory mechanisms and enable exploitation of RUNX1 as a therapeutic target in hematologic disorders. This work has the potential for immediate impact, as small molecule inhibitors of signaling pathways we hypothesize to impact RUNX1 activity are already clinically available and/or in testing.

总结 转录因子RUNX 1在永久性造血干细胞（HSC）个体发育中起重要作用， HSC维持、巨核细胞（Mk）成熟和淋巴细胞分化。RUNX 1缺陷原因 HSC和祖细胞的失衡，并且是高达30%的所有人类白血病的早期起始步骤。 RUNX 1也是高危骨髓增生异常综合征杂合失活突变的复发靶点 （MDS）。尽管RUNX 1在正常和恶性人类造血中起着中心作用，但其调节作用可能与其自身的免疫功能有关。 机制仍然不完全清楚。这种知识上的差距阻碍了利用RUNX 1的努力 作为治疗目标。我们研究的长期目标是阐明这些机制， 新的治疗策略。我们以前的工作和该领域的其他人的工作表明，RUNX 1 组装成调节其活性的大型动态多蛋白复合物。这些互动涉及 其他转录因子、表观遗传调节因子和信号传导酶。我们假设这些 相互作用受细胞信号传导途径和这些途径药理学操作的调节 可用于增强与部分RUNX 1缺乏相关的疾病中的残余RUNX 1活性。这 是基于我们的初步研究，证明稳态抑制RUNX 1活性的src家族 激酶（SFKs）和协同RUNX 1：Ets转录因子相互作用，涉及由 MEK/ERK介导的磷酸化。为了检验我们的中心假设，我们制定了以下目标： (1)鉴定在细胞成熟过程中发生的RUNX 1多蛋白复合物形成的变化， 将它们与RUNX 1活性相关联;（2）确定SFK和ERK信号通路如何调节RUNX 1 与染色质重塑复合物/转录因子的相互作用以及它们如何影响RUNX 1靶基因 （3）探索残余RUNX 1活性的药理学增强是否可以减轻RUNX 1的表达。 RUNX 1部分缺陷对小鼠造血干细胞/祖细胞失衡的影响 RUNX 1显性负性融合分子的模型。这些研究的结果应该填补重要的 关于正常RUNX 1调节机制的知识空白，并使RUNX 1能够作为 血液疾病的治疗靶点。这项工作有可能立即产生影响，因为小 我们假设影响RUNX 1活性的信号通路的分子抑制剂已经在临床上 可用和/或在测试中。