4.7 Article

Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/β-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia

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CLINICAL CANCER RESEARCH
卷 23, 期 3, 页码 789-803

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-0226

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资金

  1. National Natural Science Funds [81025021, U1301226, 81373434, 91213304]
  2. National Basic Research Program of China (973 program) [2009CB825506]
  3. Research Foundation of Education Bureau of Guangdong Province, China [cxzd1103]
  4. Research Foundation of Guangzhou Bureau of Science and Technology
  5. Fundamental Research Funds for the Central Universities
  6. Natural Science Foundation of Guangdong province [2015A030312014]
  7. Fundamental Research Funds of the State Key Laboratory of Ophthalmology [2015QN07]

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Purpose: Leukemia stem cells (LSC), which are insensitive to tyrosine kinase inhibitors (TKI), are an important source of TKI resistance and disease relapse in chronic myelogenous leukemia (CML). Obstacles to eradicating LSCs include limited understanding of the regulation network of LSCs. The current study aimed to examine the interplay between NF-kappa B and FOXM1/beta-catenin, and the effect of its chemical intervention on CML LSCs. Experimental Design: The interplay between NF-kappa B and FOXM1/beta-catenin was analyzed by reciprocal co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assay in CML cells. The effect of disturbing NF-kappa B and FOXM1/beta-catenin by niclosamide on the self-renewal capacity and survival of LSCs was evaluated in vitro in human primary CML CD34(+) cells and in vivo in CML mice. Results: Reciprocal co-IP experiments showed physical interaction of p65 and FOXM1. p65 promoted transcription of FOXM1 gene. ChIP assay revealed recruitment of p65 on the promoter of FOXM1 gene. Conversely, FOXM1 and beta-catenin positively regulated the nuclear translocation and transcriptional activity of NF-kappa B in CML cells. Niclosamide disrupted the positive feedback loop between NF-kappa B and FOXM1/beta-catenin, thereby impairing the self-renewal capacity and survival of CML LSCs. Niclosamide decreased the long-term engraftment of human CML LSCs in NOD-SCID IL2Rg chain-deficient (NOG) mice, and prolonged the survival of CML mice. Conclusions: Interaction of p65 with FOXM1/beta-catenin is critical in CML and its disruption by niclosamide eradicates LSCs. These findings may improve the understanding of a self-renewal regulatory mechanism of LSCs and offer a rationale-based approach to eliminate LSCs in CML. (C) 2016 AACR.

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