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Blood. 2012 Mar 15;119(11):2595-607. doi: 10.1182/blood-2011-10-387381. Epub 2012 Jan 24.

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

Author information

  • 1Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

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 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 p16(Ink4a) and p19(Arf) in LSCs, and knockdown of p16(Ink4a) and p19(Arf) rescues the defective colony-forming ability of HIF1α(-/-) LSCs. Compared with 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.

PMID:
22275380
[PubMed - indexed for MEDLINE]
PMCID:
PMC3311277
Free PMC Article

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