Inhibition of signal transducer and activator of transcription 5 by the inhibitor of janus kinases stimulates dormant human leukemia CD34+/CD38 cells and sensitizes them to antileukemia agents

Authors

  • Takayuki Ikezoe,

    Corresponding author
    1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
    • Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan
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    • Tel: 7plus;81-88-880-2345, Fax: +81-88-880-2348

  • Jing Yang,

    1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
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  • Chie Nishioka,

    1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
    2. Japanese Society for the Promotion of Science (JSPS), Chiyodaku, Tokyo, Japan
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  • Shinsuke Kojima,

    1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
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  • Asako Takeuchi,

    1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
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  • H. Phillip Koeffler,

    1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
    2. Japanese Society for the Promotion of Science (JSPS), Chiyodaku, Tokyo, Japan
    3. Department of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048
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  • Akihito Yokoyama

    1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
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Abstract

To verify molecular mechanisms by which leukemia stem cells (LSCs) maintain a dormant state, we explored the activity of the major prosurvival signal pathways in CD34+/CD38 compartment, supposed to contain LSCs, and CD34+/CD38+ counterparts from patients with acute myelogenous leukemia (AML, n = 11) by fluorescence-activated cell sorting (FACS). CD34+/CD38 cells expressed a greater amount of p-janus kinase 2 (JAK2) and p-signal transducer and activator of transcription 5 (STAT5) than CD34+/CD38+ counterparts in all patients except for one case. In addition, we found that CD34+/CD38 cells were relatively resistant to cytarabine- and the inhibitor of the fms-like tyrosine kinase 3 (FLT3)-mediated growth inhibition, as measured by the clonogenic assay. Interestingly, blockade of JAK2/STAT5 signaling by the specific JAK2 inhibitor AZ960 stimulated cell cycling in CD34+/CD38 cells in conjunction with downregulation of cyclin-dependent kinase inhibitor p21waf1 and sensitized these cells to the growth inhibition mediated by cytarabine and the FLT3 kinase inhibitor. Moreover, exposure of CD34+/CD38 cells to AZ960 potently induced apoptosis in parallel with downregulation of antiapoptotic protein Bcl-xL, as measured by Western blot analysis. Taken together, JAK2/STAT5 signaling may be a promising molecular target to eradicate CD34+/CD38 leukemia cells in individuals with AML.

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