Abstract
Acute myeloid leukaemia (AML) is an aggressive and mostly incurable haematological malignancy with frequent relapse after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve AML clinical outcome. Here, we aim to study the dysregulation of a particular transcription factor, E2F4, and its role in the progression of AML. In this study, human clinical data from the Gene Expression Profiling Interactive Analysis (GEPIA) revealed that increased E2F4 expression was associated with poor prognosis in AML patients. Moreover, the experimental results showed that E2F4 was aberrantly overexpressed in human AML patients and cell lines. Depletion of E2F4 inhibited the proliferation, induced the differentiation and suppressed the growth of AML cells in a nude mouse model. By contrast, overexpression of E2F4 promoted the proliferation and inhibited the differentiation of AML cells in vitro. Additionally, E2F4 expression not only is positively correlated with EZH2 but also can bind to EZH2. RNA microarray results also showed that E2F4 can regulate MAPK signalling pathway. EZH2 can reverse the inhibitory effect of E2F4 silencing on MAPK signaling pathway. In summary, our data suggest that E2F4 may be a potential therapeutic target for AML therapy.
Highlights
Acute myeloid leukaemia (AML) is characterized by uncontrolled malignant proliferation and impaired apoptosis and differentiation and accounts for 30% of leukaemia-related paediatric deaths.[1,2] leukaemia research has made great progress in diagnosis, stratification and treatment, this disease is largely incurable, and the overall 5-year survival rate is still very low at only 25%.3-7 AML patients have greatly improved after treatment, the prognosis of most patients is still not satisfactory
To determine the specific mechanism of E2F4-induced tumour cell proliferation and differentiation, we further examined the protein levels of MAPK, p-MAPK, ERK and p-ERK when E2F4 expression levels were manipulated in AML cells
The interaction between cyclins and cyclin-dependent kinases (CDKs) regulates G1 phase and cell cycle progression as well as cell division,[32,33] which are important for driving cells past checkpoints.[34]
Summary
Acute myeloid leukaemia (AML) is characterized by uncontrolled malignant proliferation and impaired apoptosis and differentiation and accounts for 30% of leukaemia-related paediatric deaths.[1,2] leukaemia research has made great progress in diagnosis, stratification and treatment, this disease is largely incurable, and the overall 5-year survival rate is still very low at only 25%.3-7 . Members of the E2F family contain many important genes that regulate the cell cycle, DNA damage repair and development.[12,13] E2F4 is a transcription factor (TF) that contributes to controlling the cell cycle. A large number of studies have shown that E2F activity is closely related to cell cycle control.[14,15] The E2F family of cell cycle regulators is classified as a family of transcriptional activators or inhibitors, but this conclusion has not been well validated.[16] E2F1-3-deficient haematopoietic cells have defects in myeloid cell differentiation, with an accumulation of granulocyte/macrophage progenitor (GMP) cells and a decrease in CD11b+ myeloid cells in the bone marrow.
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