HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells

Hypoxia-inducible factor-1α ( HIF1 α), a master transcriptional regulator of the cellular and systemic hypoxia response, is essential for the maintenance of self-renewal capacity of normal HSCs. It is still unknown whether HIF1 α has a role in survival regulation of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Using a mouse model of CML, here we report that HIF1 α plays a crucial role in survival maintenance of LSCs. Deletion of HIF1 α impairs the propagation of CML through impairing cell-cycle progression and inducing apoptosis of LSCs. Deletion of HIF1 α results in elevated expression of p16Ink4a and p19Arf in LSCs, and knockdown of p16Ink4a and p19Arf rescues the defective colony-forming ability of HIF1 α−/− LSCs. Compared with normal HSCs, LSCs appear to be more dependent on the HIF1 α pathway. Together, these results demonstrate that HIF1 α represents a critical pathway in LSCs and inhibition of the HIF1 α pathway provides a therapeutic strategy for eradicating LSCs in CML.