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이동준·김관회·김윤학·Ninib Baryawno 교수팀, Cell Death & Disease (IF: 9.685) 2022년 11월 1일 온라인 논문 게재
산화콜레스테롤은 죽상동맥경화증과 같은 염증성 질환에서 기존 연구에서 잘 알려져 있으나, 본 연구진은 산화콜레스테롤이 조혈줄기세포·전구세포 및 혈액암에서 CYP7B1 단백질 조절을 통해 활성을 특이적으로 억제함으로서 세포사멸을 유도하여 조혈줄기세포·혈액암에서 신규 바이오마커 및 유전자치료제로서 개발될 수 있는 발판을 마련했다.
이번 연구성과는 세계적인 권위지 Cell Death & Differentiation의 자매지인 『Cell Death & Disease』 (IF: 9.685) 11월 1일자 온라인에 게재됐다. 연구는 이동준·김관회·김윤학·Ninib Baryawno 교수가 교신저자, 우수연 석박사통합과정 대학원생, 이한송 석박사통합과정 대학원생이 제1저자로, 한국연구재단이 추진하는 신진후속 중견연계, MRC 선도지원센터(암세포 다양성 분자제어 연구센터) 지원 사업으로 수행했다. 또한 스웨덴 Karolinska Institutet 연구소의 Ninib Baryawno 교수팀과 공동연구를 통해 진행됐다.
논문정보:
* Paper Title: Role of reactive oxygen species in regulating 27-hydroxycholesterol-induced apoptosis of hematopoietic progenitor cells and myeloid cell lines
* https://www.nature.com/articles/s41419-022-05360-0
* First Author: Soo-Yeon Woo, Hansong Lee (School of Medicine, Pusan National University)
* Corresponding Author: Ninib Baryawno, Yun-Hak Kim, Koanhoi Kim, and Dongjun Lee (School of Medicine, Pusan National University)
* 논문 abstract
Oxysterols are oxygenated derivatives of cholesterol that contain an additional hydroxy, epoxide, or ketone group in the sterol nucleus and/or a hydroxyl group in the side chain of the cholesterol molecule. 27-Hydroxycholesterol (27HC) is a side-chain oxysterol that is oxygenated at the 27th carbon atom of cholesterol. The oxysterol (27HC) is produced via oxidation by sterol 27-hydroxylase (CYP27A1) and metabolized via oxysterol 7a-hydroxylase (CYP7B1) for bile acid synthesis in the liver. A previous study has demonstrated that treatment with the alternative Estrogen receptor alpha (ERα) ligand 27HC induces ERα-dependent hematopoietic stem cell (HSC) mobilization. In addition, Cyp27a1-deficient mice demonstrate significantly reduced 27HC levels and HSC mobilization. Here, we report that exogenous 27HC treatment leads to a substantial reduction in the hematopoietic stem and progenitor cell (HSPC) population owing to significantly increased reactive oxygen species (ROS) levels and apoptosis in the bone marrow (BM). However, 27HC does not influence the population of mature hematopoietic cells in the BM. Furthermore, exogenous 27HC treatment suppresses cell growth and promotes ROS production and apoptosis in leukemic cells. Moreover, acute myeloid leukemia (AML) patients with high CYP7B1 expression (expected to have inhibition of 27HC) had significantly shorter survival than those with low CYP7B1 expression (expected to have an elevation of 27HC). Single-cell RNA-sequencing (scRNA seq) analysis revealed that the expression of CYP7B1 was significantly increased in AML patients. Thus, our study suggests that 27HC may serve as a potent agent for regulating pools of HSPCs and may have an application as a novel therapeutic target for hematological malignancies. Collectively, pharmacological inhibition of CYP7B1 (expected to have an elevation of 27HC) would potentially have fewer long-term hematological side effects, particularly when used in combination with chemotherapy or radiation for the treatment of leukemia patients.
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