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HIF1? is required for survival maintenance of chronic myeloid leukemia stem cells.

ABSTRACT: Hypoxia-inducible factor-1? (HIF1?), 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 HIF1? 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 HIF1? plays a crucial role in survival maintenance of LSCs. Deletion of HIF1? impairs the propagation of CML through impairing cell-cycle progression and inducing apoptosis of LSCs. Deletion of HIF1? 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 HIF1?(-/-) LSCs. Compared with normal HSCs, LSCs appear to be more dependent on the HIF1? pathway. Together, these results demonstrate that HIF1? represents a critical pathway in LSCs and inhibition of the HIF1? pathway provides a therapeutic strategy for eradicating LSCs in CML.

SUBMITTER: Zhang H

PROVIDER: S-EPMC3311277 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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

Zhang Haojian H Li Huawei H Xi Hualin S HS Li Shaoguang S

Blood 20120124 11

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 ...[more]

PMID: 22275380

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Project description:Chronic myeloid leukemia (CML) is potentially fatal blood cancer, but there is an unmet need to discover novel molecular biomarkers. The hypothesis of this study aimed to elucidate the relationship of HIF1α with the redox system, Krebs cycles, notch1, and other regulatory proteins to better understand the pathophysiology and clinical relevance in chronic myeloid leukemia (CML) patients, as the molecular mechanism of this axis is still not clear. This study included CML patient samples (n = 60; 60: blood; 10: bone marrow tissues) and compared them with healthy controls (n = 20; blood). Clinical diagnosis confirmed on bone marrow aspiration, marrow trephine biopsy, and BCR/ABL1 translocation. Cases were subclassified into chronic, accelerated, and blast crises as per WHO guidelines. Molecular experiments included redox parameters, DNA fragmentation, Krebs cycle metabolites, and gene expression by RT-PCR/Western blot/LC-MS, PPI (STRING), Pearson correlation, and ROC curve analysis. Here, our findings show that p210/p190BCR/ABL1 translocation is common in all blast crisis phases of CML. Redox factor/Krebs oncometabolite concentrations were high, leading to upregulation and stabilization of HIF1α. HIF1α leads to the pathogenesis in CML cells by upregulating their downstream genes (Notch 2/4/Ikaros/SIRT1/Foxo-3a/p53, etc.). Whereas, downregulated ubiquitin proteasomal and apoptotic factors in CML pateints, can trigger degradation of HIF1α through proline hydroxylation. However, HIF1α showed a negative corelation with the notch1 pathway. Notch1 plays a tumor-suppressive role in CML and might have the potential to be used as a diagnostic marker along with other factors in CML patients. The outcome also revealed that oxidant treatment could not be effective in augmentation with conventional therapy because CML cells can enhance the levels of antioxidants for their survival. HIF1α might be a novel therapeutic target other than BCR/ABL1 translocation.

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HIF1? is required for survival maintenance of chronic myeloid leukemia stem cells.

Publications

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

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