1. Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine,Hangzhou,China,310009
2. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Cancer Center, Zhejiang University School of Medicine,Zhejiang,Hangzhou,China,310029
3. Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine,Hangzhou,China,310058
4. Division of Hematopoietic Stem Cell &amp
5. Leukemia Research, Beckman Research Institute, City of Hope, Duarte,CA,USA,91010
6. Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine,Shanghai,China,200000
Genome-wide CRISPR screening identifies critical role of PTEN in sensitivity of acute myeloid leukemia to chemotherapy[J/OL]. 浙江大学学报(英文版)(B辑:生物医学和生物技术), 2023,null.
Liming Lin, Jingjing Tao, Ying Meng, et al. Genome-wide CRISPR screening identifies critical role of PTEN in sensitivity of acute myeloid leukemia to chemotherapy[J/OL]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2023,null.
Genome-wide CRISPR screening identifies critical role of PTEN in sensitivity of acute myeloid leukemia to chemotherapy[J/OL]. 浙江大学学报(英文版)(B辑:生物医学和生物技术), 2023,null. DOI: 10.1631/jzus.B2300555.
Liming Lin, Jingjing Tao, Ying Meng, et al. Genome-wide CRISPR screening identifies critical role of PTEN in sensitivity of acute myeloid leukemia to chemotherapy[J/OL]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2023,null. DOI: 10.1631/jzus.B2300555.
Genome-wide CRISPR screening identifies critical role of PTEN in sensitivity of acute myeloid leukemia to chemotherapy
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 patients. Here, 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) radical. NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells. It induces DNA damage and caspase 3-mediated apoptosis. A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) library screen revealed that ,PTEN, gene is critical for the regulation of cell survival upon NL101 treatment. The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and MDS cells, accompanied by the activation of AKT signaling pathway. The inhibition of mTOR by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death. These 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.