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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

Ten-Eleven-Translocation 1 (TET1) plays a role in the DNA methylation process and gene activation. Recent reports suggest TET1 acts as an oncogene in leukemia development. However, the clinical relevance and biological insight of TET1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) is unknown. In this study, quantification of TET1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 360 CN-AML patients. As a result, high TET1 expression was more common in M0/M1 morphology and genes of NPM1 mutations, and underrepresented in CEBPA double allele mutations in our AML patients. In addition, we found overexpression of TET1 was associated with an inferior overall survival and event free survival in the two independent cohorts. Notably, mRNA and miRNA integrative analyses showed aberrant expression of several hub oncogenes appear to be regulated by some miRNAs like miR-127-5p, miR-494, miR-21 and miR-616 in high TET1 expressers. In conclusion, the TET1 gene expression might serve as a reliable predictor for patients survival in AML., Highlights • High TET1 mRNA expression is associated with poor survival in cytogenetically normal acute myeloid leukemia. • Several miRNAs and their targeting genes aberrantly expressed in high TET1 expressers. • These signatures can help us to decipher the poor clinical outcome of AML patients with high TET1 expression. Patients with acute myeloid leukemia had a poor survival. In this study, we found the TET1 expression can be served as a survival predictor. High expression of TET1 was associated with short survival time. A group of microRNAs and their targeting genes coexpressed in high TET1 expressers. These aberrant expressed signatures can help us to explain the poor survival of patients with high TET1 expression, and be used as the potential drug target in the future.