Role of the Cohesin complex in normal and malignant hematopoiesis

粘连蛋白复合物在正常和恶性造血中的作用

基本信息

批准号：
9979782
负责人：
AARON D VINY
金额：
$ 1.76万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979782
关键词：
3-Dimensional Acute Myelocytic Leukemia Acute leukemia Adult Affect Alleles Aneuploidy Architecture Bioinformatics Biological Assay Biological Models Biology Cell division Cells Chromatin Chromatin Loop Chromosomal Instability Chromosomes Clinical Complex Data Deacetylase Defect Development Development Plans Disease Dysmyelopoietic Syndromes Enhancers Epigenetic Process Event Foundations Gene Expression Gene Structure Genes Genetic Genetic Transcription Genetically Engineered Mouse Genotype Goals HDAC8 gene Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic stem cells Homeostasis Human Impairment Investigation Knowledge Laboratories Lead Lentivirus Vector Malignant - descriptor Malignant Neoplasms Mediating Memorial Sloan-Kettering Cancer Center Mentors Metaphase Modeling Molecular Molecular Conformation Mutate Mutation Myelogenous Myeloproliferative disease Normal Cell Nuclear Outcome Output Paper Pathway interactions Patients Pharmaceutical Chemistry Phenotype Publishing Regulatory Element Research Research Personnel Role Sampling Shapes Signal Transduction Sister Chromatid Solid Neoplasm Stress Techniques Therapeutic Time Tissue-Specific Gene Expression Tissues Training Transcription Coactivator Transcriptional Regulation Treatment Efficacy Work Xenograft procedure acute myeloid leukemia cell career development cell type cohesin cohort epigenomics gene discovery human disease improved in vitro Assay in vivo Model leukemia leukemic transformation leukemogenesis loss of function member mouse model mutant mutant mouse model new therapeutic target novel organizational structure overexpression pre-clinical programs promoter self-renewal skills stem cells targeted agent transcription factor transcriptome sequencing tumor tumorigenesis

项目摘要

Cohesin complex mutations have been identified in various solid tumors and acute myeloid leukemia. Cohesin facilitates tissue-specific gene expression through DNA looping, and its loss leads to impaired transcriptional output and impaired cell identity. As cohesin is canonically known to align and stabilize replicated chromosomes prior to cell division, mutations were initially hypothesized to drive aneuploidy. Our preliminary data shows this has not been observed. I have identified a potential alternate mechanism whereby drivers of cell-type specific gene expression and hematopoietic development are impaired through alteration in 3- dimensional nuclear organization and gene structure. While complete loss of the obligate cohesin ring member, Smc3, was lethal, we found that deletion of Stag2 and Stag1 are survivable events, however only Stag2 deletion results in myelodysplasia. I have shown that Stag1 expression increases in Stag2 deletion, likely as a redundancy/compensatory mechanism and co-deletion of Stag2 and Stag1 led to a lethal phenotype similar to our Smc3 model. Stag1 as well as the Smc3 deacetylase, Hdac8 are potential tumor-specific liabilities in cohesin mutant cancers. The aims of this project are to 1) Establish the molecular mechanism of cohesin-dependent tumorigenesis 2) Determine the effect of cohesin loss of function on cis-regulatory elements leading to altered transcriptional programming by key cohesin-targets such as PU.1/Runx1, and 3) Exploit cohesin-specific sensitivities to inhibition of STAG1 and HDAC8 with preclinical compounds. These aims will answer three important questions and will shape the focus of my independent lab: 1. Is the enhancer/cohesin landscape of AML cells different than normal cells from the same lineage? 2. Is overexpression of repressed transcription factors sufficient to overcome the transcriptional dysregulation resulting from cohesin loss of function? 3. How are tissue-specific promoter-enhancer interactions controlled by cohesin and how does gene- specific conformation change transcriptional output? Aaron Viny, an Assistant Member at MSKCC, will conduct this project as part of a career development plan, dedicating 75% of his time to research with remainder spent on clinical leukemia work. Aaron is mentored by Dr. Ross Levine, a world expert in hematologic malignancies. He is also advised by Drs. Craig Thompson Omar Abdel-Wahab, and Richard Koche at MSKCC, and Dr. Ari Melnick at Weill Cornell. Understanding of cohesin function will lead to better understanding of disease mechanisms and new modes of therapy. Aaron's training will include gaining technical laboratory skills, knowledge in the epigenetic research field, and formal training in bioinformatics and medicinal chemistry. In the short term, the project goal is to publish a paper on the findings from this research. In the long term, the goal is for developing a research program to become an independent investigator in hematologic malignancies.

粘连蛋白复合体突变已在多种实体瘤和急性髓系白血病中被发现。粘连蛋白通过 DNA 环促进组织特异性基因表达，其丢失会导致转录受损输出和受损的细胞身份。众所周知，粘连蛋白可以对齐和稳定复制的细胞分裂之前的染色体，最初假设突变导致非整倍体。我们的初步数据显示尚未观察到这一点。我已经确定了一种潜在的替代机制，通过该机制，细胞类型特异性基因表达和造血发育因 3- 的改变而受到损害维度核组织和基因结构。虽然专性粘连环完全丧失成员 Smc3 是致命的，我们发现 Stag2 和 Stag1 的删除是可存活事件，但仅 Stag2 缺失会导致骨髓增生异常。我已经证明 Stag1 表达在 Stag2 缺失中增加，可能是一种冗余/补偿机制，Stag2 和 Stag1 的共同删除导致了致命的表型类似于我们的 Smc3 模型。 Stag1 以及 Smc3 脱乙酰酶、Hdac8 具有潜在的肿瘤特异性粘连蛋白突变癌症的责任。该项目的目标是1）建立分子机制粘连蛋白依赖性肿瘤发生 2) 确定粘连蛋白功能丧失对顺式调节的影响导致关键粘连蛋白靶标（例如 PU.1/Runx1 和 3）改变转录编程的元素利用临床前化合物对 STAG1 和 HDAC8 抑制的粘连蛋白特异性敏感性。这些目标将回答三个重要问题，并将塑造我的独立实验室的重点： 1. AML 细胞的增强子/粘连蛋白景观与同一谱系的正常细胞不同吗？ 2. 被抑制的转录因子的过度表达是否足以克服转录因子的影响？粘连蛋白功能丧失导致调节失调？ 3. 组织特异性启动子-增强子相互作用如何受粘连蛋白控制，以及基因如何控制特定构象改变转录输出？ MSKCC 的助理会员 Aaron Viny 将开展该项目，作为职业发展计划的一部分，他将 75% 的时间用于研究，其余时间用于临床白血病工作。亚伦的指导者是罗斯·莱文 (Ross Levine) 博士是血液恶性肿瘤领域的世界专家。他还得到了博士的建议。克雷格·汤普森 MSKCC 的 Omar Abdel-Wahab 和 Richard Koche，以及威尔康奈尔大学的 Ari Melnick 博士。的理解粘连蛋白功能将有助于更好地了解疾病机制和新的治疗模式。亚伦的培训将包括获得技术实验室技能、表观遗传学研究领域的知识以及正式的培训。生物信息学和药物化学培训。短期内，该项目的目标是发表一篇论文这项研究的结果。从长远来看，我们的目标是开发一个研究项目，使其成为血液系统恶性肿瘤的独立研究者。