HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells
Student Authors
Haojian ZhangUMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDepartment of Medicine, Division of Hematology/Oncology
Document Type
Journal ArticlePublication Date
2012-03-15Keywords
AnimalsAnoxia
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
UMCCTS funding
Cancer Biology
Hematology
Metadata
Show full item recordAbstract
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.Source
Blood. 2012 Mar 15;119(11):2595-607. Epub 2012 Jan 24. doi: 10.1182/blood-2011-10-387381DOI
10.1182/blood-2011-10-387381Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33257PubMed ID
22275380Related Resources
ae974a485f413a2113503eed53cd6c53
10.1182/blood-2011-10-387381