Background Arsenic trioxide (ATO) is highly effective in acute promyelocytic leukemia (APL) patients, but it fails to show satisfactory efficacy in other acute myeloid leukemia (AML) patients with non-APL subtypes. Different from the APL cells, most non-APL AML cells express low levels of the ATO transporter Aquaporin-9 (AQP9) protein, making them less sensitive to ATO treatment. Recently, we found that granulocyte colony stimulating factor (G-CSF) can upregulate the expression of AQP9. We hypothesized that the pretreatment with G-CSF may enhance the antitumor effect of ATO in non-APL AML cells. In addition, we aimed to elucidate the underlying mechanisms by which G-CSF upregulates the expression of AQP9. Methods Non-APL AML cell lines including THP-1 and HL-60 were pretreated with or without G-CSF (100 ng/ml) for 24 h, followed by the treatment with ATO (2 μM) for 48 h. Cell morphology was observed under the microscope after Wright-Giemsa staining. Flow cytometry was performed to evaluate the cell apoptosis levels. The intracellular concentrations of ATO were determined by atomic fluorescence spectrometry. The mRNA and protein expression were respectively measured by quantitative reverse transcription PCR (RT-qPCR) and western blotting. Target genes were knocked down by transfection with small interfering RNA (siRNA), or overexpressed by transfection with overexpression plasmids. The cell line derived xenograft mouse model was established to confirm the results of the in vitro experiments. Results Compared with using ATO alone, the combination of G-CSF with ATO induced the cell apoptosis more dramatically. G-CSF upregulated the expression of AQP9 and enhanced the intracellular concentrations of ATO in AML cells. When AQP9 was overexpressed, it markedly enhanced the cytotoxic activity of ATO. On the other hand, when AQP9 was knocked down, it profoundly attenuated the combinational effect. Moreover, we found that the upregulation of AQP9 by G-CSF depends on the transcription factor CCAAT enhancer binding protein beta (CEBPB). We also demonstrated that the combination of G-CSF and ATO significantly inhibited tumor growth in the xenograft mouse model. Conclusions The combination of G-CSF and ATO may be a potential therapeutic strategy for AML patients.

TP53 mutation is a frequent tumor suppressor mutation and a critical prognostic indicator across studies in many malignant tumors including hematologic malignancies. However, the role of TP53 and its correlative pathway in acute myeloid leukemia (AML) is enigmatic, which may provide possible emerging strategies with the potential to improve outcomes in AML. Accordingly, we focus not only on the TP53 mutation but also on the underlying mechanisms of the mutated TP53 signal pathway. While it is now generally accepted that TP53 mutations are widely associated with a dismal prognosis, resistance to chemotherapy, and high incidence of relapse and refractory AML. Hereby, the current therapeutics targeting TP53 mutant AML are summarized in this review. This will address emerging TP53-based therapeutic approaches, facilizing the TP53-targeted treatment options.

Background: Arsenic trioxide (ATO) is widely used for acute promyelocytic leukemia (APL) treatment, but it can’t show satisfactory efficacy in non-APL leukemia. Aquaporin-9 (AQP9), a transmembrane transporter, is required for ATO uptake. Acute myeloid leukemia (AML) other than APL cells express relatively lower levels of AQP9, which limits the cytotoxic activity of ATO in those types of leukemia cells. Recently, we found that granulocyte colony stimulating factor (G-CSF) can upregulate the expression of AQP9. We hypothesized that the combination of G-CSF with ATO may enhance the antitumor effect of ATO in non-APL leukemia cells. We also aimed to elucidate the underlying mechanisms by which G-CSF upregulates the expression of AQP9.Methods: AML cell lines including THP-1 and HL-60 were pretreated with or without G-CSF (100ng/ml) for 24 hours, followed by the treatment with ATO (2μM) for 48 hours. Cell morphology was observed under microscope after Wright-Giemsa staining. Flow cytometry was performed to evaluate the cell apoptosis levels. The intracellular concentrations of ATO were determined by the atomic fluorescence spectrometry. The mRNA and protein expression were respectively measured by quantitative reverse transcription PCR (RT-qRCR) and western blotting. Target genes were knocked down by transfection with small interfering RNA (siRNA), or overexpressed by transfection with overexpression plasmids. The cell line derived xenograft mouse model was established to confirm the results of the in vitro experiments.Results: Compared with using ATO alone, the combination of ATO with G-CSF induced apoptosis in AML cells more dramatically. G-CSF upregulated the expression of AQP9 and enhanced the intracellular concentrations of ATO in AML cells. When AQP9 was overexpressed, it markedly enhanced the cytotoxic activity of ATO. On the other hand, when AQP9 was knocked down, it dramatically attenuated the combinational effect. Moreover, we found that the upregulation of AQP9 by G-CSF depends on the transcription factor CCAAT enhancer binding protein beta (CEBPB). We also demonstrated that ATO and G-CSF combination significantly inhibited the tumor growth in xenograft mouse model.Conclusions: ATO and G-CSF combination may be a potential therapeutic strategy for AML patients.