Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, PR China; Key Laboratory of Hematopoietic Malignancies, Diagnosis and Treatment, Zhejiang Province, PR China.
Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, PR China.
EBioMedicine. 2018 Dec;38:47-56. doi: 10.1016/j.ebiom.2018.11.025. Epub 2018 Nov 22.
PARP-1 plays a critical role in DNA damage repair and contributes to progression of cancer. To explore the role of PARP-1 in acute myeloid leukemia (AML), we analyzed the expression of PARP-1 in AML and its relation to the clinical prognosis. Then, we investigated the efficacy and mechanism of PARP inhibitor BMN673 (Talazoparib) combined with NL101, a novel SAHA-bendamustine hybrid in vitro and in vivo.
The expression of PARP-1 in 339 cytogenetically normal AML (CN-AML) cases was evaluated using RT-PCR. According to the expression of PARP-1, the clinical characteristics and prognosis of the patients were grouped and compared. The combination effects of BMN673 and NL101 were studied in AML cells and B-NSG mice xenograft model of MV4-11.
We found patients in high PARP-1 expression group had higher levels of blast cells in bone marrow (P = .003) and white blood cells (WBC) in peripheral blood (P = .008), and were associated with a more frequent FLT3-ITD mutation (28.2% vs 17.3%, P = .031). The overall survival (OS) and event free survival (EFS) of the high expression group were significantly shorter than those in the low expression group (OS, P = .005 and EFS, P = .004). BMN673 combined with NL101 had a strong synergistic effect in treating AML. The combination significantly induced cell apoptosis and arrested cell cycle in G2/M phase. Mechanistically, BMN673 and NL101 combinatorial treatment promoted DNA damage. In vivo, the combination effectively delayed the development of AML and prolonged survival.
High PARP-1 expression predicts poor survival in CN-AML patients. The synergistic effects of PARP inhibitor BMN673 in combination with SAHA-bendamustine hybrid, NL101, provide a new therapeutic strategy against AML. FUND: National Natural Science Foundation of China and Zhejiang Provincial Key Innovation Team.
PARP-1 在 DNA 损伤修复中发挥关键作用，并促进癌症的进展。为了探究 PARP-1 在急性髓系白血病（AML）中的作用，我们分析了 PARP-1 在 AML 中的表达及其与临床预后的关系。然后，我们研究了 PARP 抑制剂 BMN673（他拉唑帕利）与 NL101（一种新型 SAHA-苯达莫司汀杂合体）在体外和体内联合治疗的疗效和机制。
使用 RT-PCR 评估了 339 例核型正常 AML（CN-AML）病例中 PARP-1 的表达。根据 PARP-1 的表达情况，对患者的临床特征和预后进行分组和比较。在 AML 细胞和 B-NSG 小鼠 MV4-11 异种移植模型中研究了 BMN673 和 NL101 的联合作用。
我们发现高 PARP-1 表达组患者骨髓中原始细胞比例更高（P=0.003），外周血白细胞计数更高（P=0.008），并且更频繁地出现 FLT3-ITD 突变（28.2%比 17.3%，P=0.031）。高表达组的总生存期（OS）和无事件生存期（EFS）明显短于低表达组（OS，P=0.005 和 EFS，P=0.004）。BMN673 联合 NL101 对 AML 具有很强的协同作用。联合治疗显著诱导细胞凋亡，并将细胞周期阻滞在 G2/M 期。机制上，BMN673 和 NL101 联合治疗促进了 DNA 损伤。在体内，联合治疗有效地延缓了 AML 的发展并延长了生存期。
高 PARP-1 表达预示着 CN-AML 患者的生存不良。PARP 抑制剂 BMN673 与 SAHA-苯达莫司汀杂合体 NL101 的协同作用为 AML 提供了一种新的治疗策略。
国家自然科学基金和浙江省重点创新团队。
