HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells.
Blood, 2012/3/15;119(11):2595-607.
Affiliations
PMID: 22275380DOI: 10.1182/blood-2011-10-387381
Impact factor: 25.476
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.
MeSH terms
Animals; Apoptosis; Biomarkers; Blotting, Western; Bone Marrow Transplantation; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Flow Cytometry; Gene Expression Profiling; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Survival Rate
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