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

• Published in: Blood Vol. 119; no. 11; pp. 2595 - 2607
• Main Authors: Zhang, Haojian, Li, Huawei, Xi, Hualin S., Li, Shaoguang
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.03.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Animals; Apoptosis; Biological and medical sciences; Biomarkers - metabolism; Blotting, Western; Bone Marrow Transplantation; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Flow Cytometry; Gene Expression Profiling; Hematologic and hematopoietic diseases; Hypoxia - metabolism; Hypoxia - pathology; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - mortality; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Neoplasia; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Survival Rate; Myeloproliferative syndrome; Hematology; Stem cell; Chronic myelogenous leukemia; Malignant hemopathy; Survival; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-10-387381

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 p16Ink4a and p19Arf in LSCs, and knockdown of p16Ink4a and p19Arf 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.