HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells
Department of Medicine, Division of Hematology/Oncology; Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Animals; Anoxia; Apoptosis; Biological Markers; Blotting, Western; Bone Marrow Transplantation; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Flow Cytometry; Gene Expression Profiling; 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
Cancer Biology | Hematology
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.
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Citation: Blood. 2012 Mar 15;119(11):2595-607. Epub 2012 Jan 24. doi: 10.1182/blood-2011-10-387381
DOI of Published Version
Zhang, Haojian; Li, Huawei; Xi, Hualin S.; and Li, Shaoguang, "HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells" (2012). GSBS Student Publications. 1790.