Hypoxic exposure activates the B cell-specific Moloney murine leukaemia virus integration site 1/PI3K/Akt axis and promotes EMT in leukaemia stem cells.

Acute myeloid leukemia (AML) is a malignant tumor of the immature myeloid hematopoietic cells in the bone marrow. Disease recurrence driven by leukaemia stem cells (LSCs), a sub-population of leukaemia cells presenting self-renewal capacity and differentiation potential, is a major problem in the treatment of AML. Although a hypoxic microenvironment is considered to promote AML malignant behaviours and is considered a potential therapeutic target, the effect of hypoxic stimulation of LSCs is still largely unknown. Therefore, the present study analysed the effects of hypoxia on the malignant behaviours of LSCs. Hypoxia exposure upregulated hypoxia-inducible factor (HIF)-1α, which upregulated the transcription of B cell-specific Moloney murine leukaemia virus integration site 1 (BMI-1). Hypoxia exposure also activated the PI3K/Akt pathway and promoted the epithelial mesenchymal transition (EMT) in LSCs via hypoxia-mediated activation of HIF-1α. BMI-1 served an important role in the hypoxia-induced activation of the PI3K/Akt pathway and the promotion of EMT. Hypoxia exposure promoted chemoresistance against cytarabine arabinoside by inducing HIF-1α, thus activating the transcriptional activity of HIF-1α. Knockdown of BMI-1 disrupted hypoxia-induced chemoresistance in LSCs, indicating that HIF-1α-induced BMI-1 has a role in hypoxia-promoted malignant behaviours. Furthermore, it was demonstrated that induced BMI-1 inhibits the self-renewal capacity in LSCs under hypoxic conditions. The present study provides evidence demonstrating that hypoxia exposure regulates LSCs by activating HIF-1α/BMI-1 signalling, in turn modulating PI3K/Akt signalling and EMT. These results highlight potentially novel therapeutic targets of LSCs to improve the treatment of AML.