Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy

作     者：Liming LIN Jingjing TAO Ying MENG Yichao GAN Xin HE Shu LI Jiawei ZHANG Feiqiong GAO Dijia XIN Luyao WANG Yili FAN Boxiao CHEN Zhimin LU Yang XU Liming LIN;Jingjing TAO;Ying MENG;Yichao GAN;Xin HE;Shu LI;Jiawei ZHANG;Feiqiong GAO;Dijia XIN;Luyao WANG;Yili FAN;Boxiao CHEN;Zhimin LU;Yang XU

作者机构：Department of Hematologythe Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Zhejiang Provincial Key Laboratory of Pancreatic Diseasethe First Affiliated Hospital and Institute of Translational MedicineCancer CenterZhejiang University School of MedicineHangzhou 310029China Institute of GeneticsZhejiang UniversityHangzhou 310058China Division of Hematopoietic Stem Cell&Leukemia ResearchBeckman Research Institute of City of HopeDuarteCA 91010USA Department of HematologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China 

出 版 物：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 (浙江大学学报（英文版）B辑（生物医学与生物技术）)

年 卷 期：2024年第25卷第8期

页      面：700-710页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the Zhejiang Provincial Natural Science Foundation of China(No.LY21H080005) the National Natural Science Foundation of China(Nos.81572920 and 82100171) 

主　　题：Genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)library Phosphatase and tensin homologous(PTEN) Rapamycin Acute myeloid leukemia(AML) Chemotherapy 

摘      要：Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia(AML)in recent years,chemotherapy still remains the mainstay of treatment and the overall survival is poor in most ***,we demonstrated the antileukemia activity of a novel small molecular compound NL101,which is formed through the modification on bendamustine with a suberanilohydroxamic acid(SAHA)***101 suppresses the proliferation of myeloid malignancy cells and primary AML *** induces DNA damage and caspase 3-mediated apoptosis.A genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)library screen revealed that phosphatase and tensin homologous(PTEN)gene is critical for the regulation of cell survival upon NL101 *** knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome(MDS)cells,accompanied by the activation of protein kinase B(AKT)signaling *** inhibition of mammalian target of rapamycin(mTOR)by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell *** findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.