Role of the Cohesin complex in normal and malignant hematopoiesis

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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.