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Sensitivity And Resistance To Therapy

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

Leukemia volume 22, pages 1899–1908 (2008)Cite this article

Abstract

Chemotherapy resistance is a major challenge in acute myeloid leukemia (AML). Besides the P-glycoprotein efflux, additional cellular factors may contribute to drug resistance in AML. c-Jun N-terminal kinase (JNK) is activated after exposure of cells to chemotherapeutics. We asked whether chemoresistance in AML is attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative cell lines U937R and URD40 showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. RNA interference-based depletion of JNK1 in drug-sensitive U937 cells made them chemoresistant, whereas selective restoration of the inactive JNK pathway in the resistant U937R cells sensitized them to anthracyclines. Short-term in vitro exposure of primary AML cells (n=29) to daunorubicin showed a strong correlation between the in vitro pharmacodymanic changes of phospho-JNK levels and the response of patients to standard induction chemotherapy (P=0.012). We conclude that JNK activation failure confers another mechanism of anthracycline resistance in AML. Elucidating the ultimate mechanisms leading to JNK suppression in chemoresistant AML may be of major therapeutic value.

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Acknowledgements

We thank Dr Argyris Symeonidis, Dr Alexandra Symeonidis-Kouraklis and Dr Panagiotis Zikos for their support with patient material and file information. We thank Dr John Kyriakis (Tufts University School of Medicine) for his generous gift of PEBG-SEKED construct. We thank Prof Panagiota Matsouka (Patras University) for critical discussions. We thank Lorna Pherson for excellent laboratory assistance, Maria Themeli for critical discussions and Aristotelis Klamargias for help in statistical analysis.

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Authors and Affiliations

  1. Department of Internal Medicine, Hematology Division, University Medical School of Patras, Patras, Greece

    E D Lagadinou, P G Ziros, O A Tsopra, D Kokkinou, E Thanopoulou, M Karakantza, A Spyridonidis & N C Zoumbos

  2. Division of Pharmacology-Pharmacotechnology, Foundation for Biomedical Research, Academy of Athens, Athens, Greece

    K Dimas & P Pantazis

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Lagadinou, E., Ziros, P., Tsopra, O. et al. c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia. Leukemia 22, 1899–1908 (2008). https://doi.org/10.1038/leu.2008.192

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