TAF1 inhibitor Bay-299 induces cell death in acute myeloid leukemia

Background: Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies. The cure rate of currently intensive chemotherapy in AML was only 40% or less, and there is an urgent need to develop novel effective therapeutic targets or drugs. The TATA-box binding protein associated factor 1 (TAF1) plays important roles in transcriptional regulation and leukemogenesis. However, the potential of TAF1 as a therapeutic target for AML remains unclear. The present study examined the effects of the TAF1 inhibitor Bay-299 on AML cells and the underlying molecular mechanisms. Methods: The expression of TAF1 in various types of tumors was analyzed using The Cancer Genome Atlas (TCGA) and the UALCAN database. The effects of Bay-299 on cell proliferation were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Cell death, EdU incorporation, and cell differentiation were detected using flow cytometry. Western blot analysis was utilized to confirm the activation of the apoptotic pathway. Expression of cell cycle and cell death-related genes was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Results: Analysis of the public databases showed that TAF1 expression was elevated in multiple types of tumors. Treatment of AML cells with the TAF1 inhibitor Bay-299 resulted in a remarkable inhibition of cell growth, increased cell death, reduced Edu incorporation, and increased cell differentiation. The apoptosis inhibitor Z-VAD and the receptor-interacting protein kinase 1 (RIPK1) inhibitor Nec-2 could rescue cell death induced by Bay-299. Bay-299 treatment increased the cleavage of key pro-apoptotic proteins, and this effect was ameliorated by administration of Z-VAD and Nec-2. Moreover, Bay-299 treatment was associated with increased expression of cell cycle inhibitor genes and multiple pyroptosis-promoting genes, contributing to the phenotypes observed in AML cell lines. Conclusions: The TAF1 inhibitor Bay-299 induced AML cell death through multiple mechanisms and may be a promising candidate for the treatment of patients with AML.

Automated summary

The TAF1 inhibitor Bay-299 shows potential as a promising candidate for the treatment of patients with AML by inducing cell death through multiple mechanisms, including inhibiting cell growth, promoting cell death and differentiation, and increasing the expression of cell cycle inhibitor genes and pyroptosis-promoting genes.