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대학원 세미나

04/18(목)16시 연사:윤희영
작성자 관리자조회수 212날짜 2019.04.12
일시: 04월 18일(목) 4:00PM

장소 : 벤처관 711호

연사: 윤희영(마크로젠 (선임연구원), 하버드의대 (Research Fellow))

제목:Understanding of NOTCH1 resistant T-cell acute lymphoblastic leukemia

내용: Resistance to therapy presents a major challenge in cancer treatment today, and novel approaches to identify and overcome the mechanisms that cause resistance are desperately needed for improving outcome. Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy in children and young adults that frequently becomes treatment-refractory and relapses. The NOTCH1 pathway is a key oncogenic driver in T-ALL, and is aberrantly activated in more than 50% of the cases. Many therapies targeting Notch activation, including gamma secretase inhibitors (GSI), have been developed and tested. Yet, the rapid development of resistance that occurs with Notch inhibition in vivo has so far prevented the translation of these inhibitors into the clinical setting. Using a model of therapeutic resistance to Notch inhibition in T-ALL, we have recently established epigenetic resistance mechanisms in leukemia for the first time. Rare GSI-tolerant ‘persister’ cells are already present in the naïve T-ALL population – existing in dynamic equilibrium with GSI-sensitive cells – and give rise to the GSI-resistant population after prolonged treatment with GSI. Persisters exhibit an altered epigenetic state consistent with both, global chromatin compaction and local changes at enhancers of genes that are critically important for cell survival and lineage defining genes.
In this study, we develop a research proposal that aims to determine the mechanisms underlying the epigenetic state transitions in drug resistant T-cell acute lymphoblastic leukemia (T-ALL), which will have immediate implications for treatment of resistant disease.
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