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 Effects

PARP-1 plays a critical role in DNA damage repair and contributes to progression of cancer. To address the role of PARP-1 in AML, we analyzed the expression of PARP-1 in acute myeloid leukemia (AML) using RT-PCR. We found high expressers had higher levels of blast cells in bone marrow (P=0.003) and WBC in peripheral blood (P=0.008) and were associated with a more frequent FLT3-ITD mutation (28.2% vs 17.3%, P= 0.031). The overall survival (OS) and event free survival (EFS) of the high expression group were significantly shorter than those of the low expression group (P=0.005 and P=0.004, respectively). High PARP-1 expression predicts poor survival in AML patients. 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 combination significantly enhanced apoptosis of AML cells and induced G2/M cell cycle arrest. Mechanistically, BMN673 and NL101 combinatorial treatment promoted DNA damage. In vivo, the combination effectively delayed the development of AML and prolonged survival.The synergistic effects of PARP inhibitor BMN673 in combination with SAHA-bendamustine hybrid, NL101, provide a new therapeutic strategy against AML.