Targeting HMGCS1 restores chemotherapy sensitivity in acute myeloid leukemia  

作　　者：Cheng Zhou Jue Li Xiaofan Sun Liang Zhao Huien Zhan Hui Liang Peng Fang Tuo Zhang Qiongzhi He Juan Du Hui Zeng 

机构地区：[1]Department of Hematology,The First Affiliated Hospital of Jinan University,Guangzhou,Guangdong 510630,China [2]Department of Hematology,Xiangya Hospital,Central South University,Changsha,Hunan 410008,China [3]Genomic Core,Weill Cornell Medical College,New York,NY 10021,USA [4]Geneplus-Beijing Institute,Beijing 102206,China

出　　处：《Blood Science》2024年第3期11-22,共12页血液科学（英文）

基　　金：supported by the National Natural Science Foundation of China to H.Z.(Grant Nos.81770184,81970143,and 82270167)and L.Z.(Grant No.81800174);the Talent Young Program of Guangdong Province(2021B1515020017),and the Leading Talents Program from The First Affiliated Hospital of Jinan University to H.Z.

摘　　要：Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.

关 键 词：Chemotherapy sensitivity HMGCS1 MAPK pathway Relapsed and refractory AML Targeted therapy 

分 类 号：R733.71[医药卫生—肿瘤]