1.Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous(PTEN)in sensitivity of acute myeloid leukemia to chemotherapy
LIN LIMING ; TAO JINGJING ; MENG YING ; GAN YICHAO ; HE XIN ; LI SHU ; ZHANG JIAWEI ; GAO FEIQIONG ; XIN DIJIA ; WANG LUYAO ; FAN YILI ; CHEN BOXIAO ; LU ZHIMIN ; XU YANG
Journal of Zhejiang University. Science. B 2024;25(8):700-710,中插5-中插6
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 phosphatase and tensin homologous(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 myelodysplastic syndrome(MDS)cells,accompanied by the activation of protein kinase B(AKT)signaling pathway.The inhibition of mammalian target of rapamycin(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.
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