尽管近年来治疗急性髓系白血病（AML）的新型靶向药物的开发取得了重大进展，但化疗仍然是治疗的主要手段，大多数患者的总体生存率较差。在这里，我们证明了一种新型小分子化合物 NL101 的抗白血病活性，该化合物是通过用辛二苯异羟肟酸 (SAHA) 基团对苯达莫司汀进行修饰而形成的。 NL101 抑制骨髓恶性肿瘤细胞和原发性 AML 细胞的增殖。它诱导 DNA 损伤和 caspase 3 介导的细胞凋亡。全基因组规律聚集的短回文重复序列 (CRISPR) 文库筛选显示，磷酸酶和张力蛋白同源 (PTEN) 基因对于 NL101 处理后细胞存活的调节至关重要。敲除或抑制 PTEN 可显着减少 NL101 诱导的 AML 和骨髓增生异常综合征 (MDS) 细胞凋亡，同时激活蛋白激酶 B (AKT) 信号通路。雷帕霉素对哺乳动物雷帕霉素靶点（mTOR）的抑制增强了 AML 细胞对 NL101 诱导的细胞死亡的敏感性。这些发现揭示了 PTEN 蛋白表达是 NL101 化疗敏感性的主要决定因素，并提供了一种联合 NL101 和雷帕霉素治疗 AML 的新策略。

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.