Role of the Cohesin complex in normal and malignant hematopoiesis

粘附素复合体突变在各种实体瘤和急性髓系白血病中已被发现。粘合 通过DNA环促进组织特异性基因的表达，其缺失会导致转录受损 输出和受损的细胞识别。因为粘附素是公认的对齐和稳定复制的 染色体在细胞分裂之前，突变最初被假设为驱动非整倍体。我们的预赛 数据显示，这一点尚未被观察到。我已经确定了一种潜在的替代机制，即司机 细胞类型特异性基因表达和造血发育因3-亚基的改变而受损 次元核组织和基因结构。当预留的粘附素环完全丧失时 成员Smc3是致命的，我们发现STAG2和Stag1的缺失是可存活的事件，但只有 STAG2缺失会导致骨髓发育不良。我已经证明了Stag1的表达在STAG2缺失时增加， 可能是一种冗余/补偿机制，STAG2和Stag1的共同缺失导致了致命的表型 类似于我们的Smc3型号。Stag1和Smc3脱乙酰酶、Hdac8是潜在的肿瘤特异性基因 粘附素突变癌症的风险。本项目的目的是：1)建立细胞免疫的分子机制 粘附素依赖的肿瘤发生2)决定粘附素功能丧失对顺式调节的影响 导致关键粘附素靶标如PU.1/RUNX1和3的转录编程改变的元件) 利用临床前化合物对抑制STAG1和HDAC8的粘附素特异性敏感性。这些 AIMS将回答三个重要问题，并将塑造我独立实验室的重点： 1.急性髓系白血病细胞的增强子/粘附素图谱与来自同一谱系的正常细胞是否不同？ 2.抑制转录因子的过度表达是否足以克服转录 凝集素功能丧失导致的调节失调？ 3.组织特异性启动子-增强子相互作用是如何由粘附素控制的，以及基因如何- 特定构象改变转录输出？ MSKCC的助理成员亚伦·维尼将把这个项目作为职业发展计划的一部分来实施， 他将75%的时间用于研究，其余的时间用于临床白血病工作。Aaron的导师是 世界血液系统恶性肿瘤专家罗斯·莱文博士说。克雷格·汤普森博士也为他提供了建议 Omar Abdel-Wahab，MSKCC的Richard Koche，以及Weill Cornell的Ari Melnick博士。了解 粘附素功能将有助于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、表观遗传学研究领域的知识和正规 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，目标是开发一项研究计划，使其成为 血液系统恶性肿瘤的独立调查者。

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.