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Background

Acute myeloid leukemia (AML) is a highly heterogeneous disease with poor clinical prognosis, especially to cytogenetically normal AML(CN-AML)patients, which belong to moderate prognosis group. The clinical outcomes of them are not consistent. Therefore, further exploration of novel biomarkers and development of new anti-tumor drugs is urgently needed. Recently, accumulating evidence have emerged and demonstrated that branched-chain amino acids (BCAA) are essential for tumor growth and proliferation. Branched-chain aminotransferase 1(BCAT1), a BCAA metabolic enzyme, which correlates with cancer aggression, not only that, it has been reported that overexpression of BCAT1in leukemia cells decreased intracellular αKG levels, showed the characteristics of stem cells and displayed a phenotype like cases carrying IDH mutations. By limiting intracellular αKG, BCAT1high expression AML cells prone to cause an increase in DNA damage probably via suppressing homologous recombination.

PARP-1 plays a critical role in DNA damage repair and contributes to progression of cancer. To address the role of PARP-1in AML, we analyzed the expression of PARP-1in 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-1expression 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 vitroand 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.

IDH1and IDH2mutations are frequently identified in older patients with AML.With the development and application of IDH inhibitor, the prognostic significance of these mutations in old patients is of primary importance. To assess the impact on clinic outcome, we analyzed 224 older (> 60 years) patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) similarly treated with intensive induction chemotherapy. Our analysis identified IDH1and/or IDH2(IDH1/2), IDH1or IDH2mutations in 63(28%), 29(12.9%) and 35(15.6%) patients, respectively. In general, IDH1and IDH2mutations were mutually exclusive, with only one patient having both IDH1R132C and IDH2R140Q mutations. IDH2R172 mutations were exclusive with all other mutations analyzed (NPM1, CEBPA, DNMT3A, IDH1and FLT3-ITD). There was a strong interaction between IDH2mutation and NPM1mutational status. Concurrent presence of IDH2R140 and NPM1mutations was independently associated with longer overall survival (OS; P=0.038, HR=0.42) and event free survival (EFS; P=0.034, HR=0.46) compared to the wild type counterpart in multivariable analyses. In contrast, IDH1mutations were independently associated with shorter OS (P=0.004, HR=1.98) and EFS (P=0.014, HR=1.72) in multivariable analyses. Notably, IDH1R132 mutations harbored higher levels of total 2-hydroxyglutarate compared to IDH2R140Q mutations. Patients with IDH1mutations or IDH2R140 and NPM1mutations harbored also distinct miRNA-expression signatures. Future studies will establish whether these difference between IDH1and IDH2mutations will be relevant with respect to response of the respective subsets of patients to the emerging therapies with IDH1 and IDH2 inhibitors.