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
✍ Scribed by Takayuki Ikezoe; Jing Yang; Chie Nishioka; Shinsuke Kojima; Asako Takeuchi; H. Phillip Koeffler; Akihito Yokoyama
- Book ID
- 102863139
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- French
- Weight
- 903 KB
- Volume
- 128
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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 p21^waf1^ 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.