High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effectsResearch in context
Xia Li,
Chenying Li,
Jingrui Jin,
Jinghan Wang,
Jiansong Huang,
Zhixin Ma,
Xin Huang,
Xiao He,
Yile Zhou,
Yu Xu,
Mengxia Yu,
Shujuan Huang,
Xiao Yan,
Fenglin Li,
Jiajia Pan,
Yungui Wang,
Yongping Yu,
Jie Jin
Affiliations
Xia Li
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
Chenying Li
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
Jingrui Jin
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
Jinghan Wang
Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, PR China
Jiansong Huang
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
Zhixin Ma
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
Xin Huang
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
Xiao He
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
Yile Zhou
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
Yu Xu
Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, PR China
Mengxia Yu
Department of Hematology, Hangzhou First People's Hospital, Hangzhou, PR China
Shujuan Huang
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
Xiao Yan
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
Fenglin Li
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
Jiajia Pan
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
Yungui Wang
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
Yongping Yu
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
Jie Jin
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; Corresponding author at: Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, PR China.
Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Keywords: PARP-1, Acute myeloid leukemia, PARP inhibitor, SAHA-bendamustine hybrid
