Role of the Cohesin complex in normal and malignant hematopoiesis

已经在各种实体瘤和急性髓性白血病中鉴定了粘着蛋白复合物突变。黏结蛋白 通过DNA环促进组织特异性基因表达，其缺失导致转录受损， 输出和受损的细胞身份。由于粘附素是公认的对齐和稳定复制 在细胞分裂之前，突变最初被假设为驱动非整倍性。我们的初步 数据显示，这一点尚未观察到。我已经确定了一种潜在的替代机制， 细胞类型特异性基因表达和造血发育通过3- 三维核组织和基因结构。当专性黏连蛋白环完全丧失时， 成员Smc 3是致死性的，我们发现Stag 2和Stag 1的缺失是可存活的事件，但只有 Stag 2缺失导致骨髓发育不良。我已经证明了Stag 2缺失时Stag 1的表达增加， 可能作为冗余/补偿机制，Stag 2和Stag 1的共缺失导致致死表型 类似于我们的SMC 3模型。Stag 1以及Smc 3脱乙酰酶、Hdac 8是潜在的肿瘤特异性的 cohesin突变型癌症的风险本课题的主要目的是：1）建立 2）确定粘连蛋白功能丧失对顺式调节肿瘤发生的影响， 通过关键的粘附蛋白靶点如PU.1/Runx 1导致转录编程改变的元件，和3） 利用临床前化合物抑制STAG 1和HDAC 8的粘附素特异性敏感性。这些 aims将回答三个重要的问题，并将塑造我的独立实验室的重点： 1. AML细胞的增强子/粘附素景观与来自相同谱系的正常细胞不同吗？ 2.抑制转录因子的过度表达是否足以克服转录抑制因子的转录抑制作用？ 内聚蛋白功能丧失导致的调节异常 3.组织特异性启动子-增强子相互作用是如何被粘附素控制的，基因- 特异性构象改变转录产物？ 亚伦维尼，在MSKCC助理成员，将进行这个项目作为职业发展计划的一部分， 他75%的时间用于研究，其余时间用于临床白血病工作。亚伦是由 博士罗斯·莱文，世界血液恶性肿瘤专家。他还得到了克雷格汤普森博士的建议 Omar Abdel-Wahab，MSKCC的Richard Koche，以及Weill Cornell的Ari Melnick博士。了解 粘着蛋白功能将导致更好地理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，在表观遗传学研究领域的知识， 生物信息学和药物化学方面的培训。在短期内，该项目的目标是发表一篇关于 这项研究的发现。从长远来看，我们的目标是发展一个研究计划，成为一个 血液恶性肿瘤的独立研究者。

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.