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

Haojian Zhang, Huawei Li, Hualin S Xi and Shaoguang Li

Abstract

Hypoxia-inducible factor-1α (HIF1α), a master transcriptional regulator of the cellular and systemic hypoxia response, is essential for the maintenance of self-renewal capacity of normal hematopoietic stem cells (HSCs). It is still unknown whether HIF1α 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 HIF1α plays a crucial role in survival maintenance of LSCs. Deletion of HIF1α impairs the propagation of CML through impairing cell cycle progression and inducing apoptosis of LSCs. Deletion of HIF1α results in elevated expression of p16Ink4a and p19Arf in LSCs, and knockdown of p16Ink4a and p19Arf rescues the defective colony-forming ability of HIF1α-/- LSCs. Compared to normal HSCs, LSCs appear to be more dependent on the HIF1α pathway. Together, these results demonstrate that HIF1α represents a critical pathway in LSCs and inhibition of the HIF1α pathway provides a therapeutic strategy for eradicating LSCs in CML.

  • Submitted October 21, 2011.
  • Accepted December 31, 2011.