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Sensitivity and Resistance to Therapy

Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene

Leukemia volume 24, pages 1631–1640 (2010)Cite this article

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Abstract

Imatinib induces complete molecular response in patients with chronic myeloid leukemia (CML) and chronic eosinophilic leukemia (CEL). However, development of resistance to imatinib has emerged as an important clinical problem for molecular-targeted therapy in CML and CEL. In this study, we have established the imatinib-resistant CEL EOL-1 sub-lines (designated as EOL-1R) by culturing cells with increasing concentrations of imatinib for 6 months. Interestingly, EOL-1R cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene. Exposure of EOL-1R cells to imatinib failed to dephosphorylate AKT, ERK and STAT5, although PDGFRα was effectively inactivated. The forced expression of PTEN negatively regulated these signal pathways and sensitized EOL-1R cells to imatinib. Notably, hypermethylation of the promoter region of the PTEN gene in association with the downregulation of this gene's transcripts was identified in imatinib-resistant leukemia cells isolated from individuals with CEL, CML and Philadelphia-positive acute lymphoblastic leukemia. In addition, anti-epigenetic agents restored PTEN expression, resulting in the sensitization of EOL-1R cells to imatinib. Taken together, epigenetic silence of PTEN is one of the mechanisms that cause drug resistance in individuals with leukemia after exposure to imatinib. Anti-epigenetic agents may be useful for overcoming drug resistance in such a case.

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Acknowledgements

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture Sports, Science, and Technology of Japan (to TI), The Kochi University President's Discretionary Grant (to TI), Takeda Science Foundation (to TI), AstraZeneca Research Grant 2008 (to TI) and Sagawa Foundation for Promotion of Cancer Research (to TI). CN is grateful for a JSPS Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science.

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  1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan

    C Nishioka, T Ikezoe, J Yang & A Yokoyama

  2. Japanese Society for the Promotion of Science (JSPS), Tokyo, Japan

    C Nishioka

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Nishioka, C., Ikezoe, T., Yang, J. et al. Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene. Leukemia 24, 1631–1640 (2010). https://doi.org/10.1038/leu.2010.145

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