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.
近年来，在急性髓系白血病（AML）治疗的新型靶向药物开发方面虽取得显著进展，但目前化疗仍然是主要的治疗手段，大多数患者的总体生存率仍较低。本研究展示了一种新型小分子化合物NL101的抗白血病活性，该化合物是通过在苯达莫司汀的侧链加上辛二酰苯胺异羟肟酸（SAHA）基团修饰形成。NL101能抑制髓系恶性肿瘤细胞和原发性AML细胞的增殖，并可诱导DNA损伤和半胱天冬酶3介导的细胞凋亡。全基因组CRISPR文库筛选发现，PTEN基因在NL101处理后调节细胞存活中起到关键作用。PTEN敲除或抑制伴随着AKT信号通路的激活，可显著降低AML和骨髓增生异常综合征（MDS）细胞对NL101诱导的凋亡作用。雷帕霉素联用可通过抑制mTOR增强AML细胞对NL101诱导细胞死亡的敏感性。上述发现揭示了PTEN蛋白的表达是NL101化疗敏感性的主要决定因素，这提供了一种新的治疗策略，为NL101与雷帕霉素联合治疗AML提供了理论依据。.
近年来，在急性髓系白血病（AML）治疗的新型靶向药物开发方面虽取得显著进展，但目前化疗仍然是主要的治疗手段，大多数患者的总体生存率仍较低。本研究展示了一种新型小分子化合物NL101的抗白血病活性，该化合物是通过在苯达莫司汀的侧链加上辛二酰苯胺异羟肟酸（SAHA）基团修饰形成。NL101能抑制髓系恶性肿瘤细胞和原发性AML细胞的增殖，并可诱导DNA损伤和半胱天冬酶3介导的细胞凋亡。全基因组CRISPR文库筛选发现，PTEN基因在NL101处理后调节细胞存活中起到关键作用。PTEN敲除或抑制伴随着AKT信号通路的激活，可显著降低AML和骨髓增生异常综合征（MDS）细胞对NL101诱导的凋亡作用。雷帕霉素联用可通过抑制mTOR增强AML细胞对NL101诱导细胞死亡的敏感性。上述发现揭示了PTEN蛋白的表达是NL101化疗敏感性的主要决定因素，这提供了一种新的治疗策略，为NL101与雷帕霉素联合治疗AML提供了理论依据。
Keywords: Acute myeloid leukemia (AML); Chemotherapy; Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) library; Phosphatase and tensin homologous (PTEN); Rapamycin.