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:
    9754012
  • 负责人:
  • 金额:
    $ 25.68万
  • 依托单位:
  • 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 2023-07-31
  • 项目状态:
    已结题

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.
在各种实体瘤和急性髓样白血病中已经鉴定出粘着蛋白复合物突变。粘着蛋白 通过DNA循环促进组织特异性基因表达,其损失导致转录受损 输出和细胞身份受损。由于粘蛋白在典型上已知可以对齐和稳定复制 细胞分裂之前的染色体,最初假设突变驱动非整倍性。我们的初步 数据表明尚未观察到这一点。我已经确定了一种潜在的替代机制 细胞类型的特异性基因表达和造血发育通过3-的改变而受到损害 维核组织和基因结构。虽然完全损失了强制性粘蛋白环 成员SMC3是致命的,我们发现Stag2和Stag1的缺失是可生存的事件,但是只有 Stag2缺失导致骨髓增生。我已经表明,stag1表达在stag2删除中增加, 可能是冗余/补偿机制以及stag2和stag1的脱落导致致命表型 类似于我们的SMC3模型。 STAG1以及SMC3脱乙酰基酶,HDAC8是潜在的肿瘤特异性 粘着蛋白突变体癌的负债。该项目的目的是1)建立分子机制 依赖于粘着蛋白的肿瘤发生2)确定粘蛋白功能丧失对顺式调节的影响 元素导致通过关键粘着蛋白 - 靶标(例如pu.1/runx1和3)改变转录编程的元素 利用粘合素特异性的敏感性对用临床前化合物抑制STAG1和HDAC8。这些 AIMS将回答三个重要问题,并将塑造我的独立实验室的重点: 1。与同一谱系的AML细胞的增强子/粘着素景观是否不同? 2。是足以克服转录的抑制转录因子的过表达 功能的粘着蛋白丧失引起的失调? 3。如何由粘蛋白控制的组织特异性启动子增强剂相互作用以及基因如何 特定构象会改变转录输出? MSKCC的助理成员Aaron Viny将作为职业发展计划的一部分进行该项目, 将他75%的时间用于研究临床白血病工作的剩余时间。亚伦由 罗斯·莱文(Ross Levine)博士,血液系统恶性肿瘤的世界专家。博士也建议他。克雷格·汤普森(Craig Thompson) MSKCC的Omar Abdel-Wahab和Richard Koche和Weill Cornell的Ari Melnick博士。理解 粘着素功能将使人们更好地了解疾病机制和新的治疗方式。亚伦的 培训将包括获得技术实验室技能,表观遗传研究领域的知识以及正式 生物信息学和药物化学培训。在短期内,项目目标是发表有关 这项研究的发现。从长远来看,目标是制定研究计划成为 血液系统恶性肿瘤的独立研究者。

项目成果

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AARON D VINY其他文献

AARON D VINY的其他文献

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{{ truncateString('AARON D VINY', 18)}}的其他基金

The role of the cohesin complex in hematopoietic transformation and leukemia maintenance
粘连蛋白复合物在造血转化和白血病维持中的作用
  • 批准号:
    10780841
  • 财政年份:
    2023
  • 资助金额:
    $ 25.68万
  • 项目类别:
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
  • 批准号:
    10452554
  • 财政年份:
    2018
  • 资助金额:
    $ 25.68万
  • 项目类别:
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
  • 批准号:
    9979782
  • 财政年份:
    2018
  • 资助金额:
    $ 25.68万
  • 项目类别:
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
  • 批准号:
    10327059
  • 财政年份:
    2018
  • 资助金额:
    $ 25.68万
  • 项目类别:
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
  • 批准号:
    10227020
  • 财政年份:
    2018
  • 资助金额:
    $ 25.68万
  • 项目类别:

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The role of the cohesin complex in hematopoietic transformation and leukemia maintenance
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