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Sensitivity and Resistance to Therapy

Rapamycin reverses NPM-ALK-induced glucocorticoid resistance in lymphoid tumor cells by inhibiting mTOR signaling pathway, enhancing G1 cell cycle arrest and apoptosis

Leukemia volume 22, pages 2091–2096 (2008)Cite this article

Abstract

The anaplastic lymphoma kinase (ALK) is an oncogene product involved in hematopoietic and non-hematopoietic malignancies. Recent studies have demonstrated that nucleophosmin (NPM)-ALK, originated from the fusion of NPM and ALK genes, causes cell transformation through diverse mechanisms. Here, we show a novel mechanism by which NPM-ALK transforms lymphoid tumor cells to become resistant to glucocorticoid (GC) or dexamethasone (Dex) treatment. Transformed BaF3 cells by NPM-ALK were much more resistant to Dex compared with their parental cells, and concurrently had a constitutive activation of mammalian target of rapamycin (mTOR) signaling, as evidenced by hyperphosphorylation of its downstream effectors, p70 S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The mTOR inhibitor rapamycin suppressed activation of p70S6K in BaF3/NPM-ALK cells and reversed GC resistance by synergistically inhibiting mTOR signaling pathway, enhancing cell cycle arrest at G1 phase and promoting apoptotic cell death. In conclusion, our data indicate that the ALK fusion kinase, NPM-ALK, induces GC resistance by activating mTOR signaling, and addition of mTOR inhibitors to the chemotherapeutic regimen of ALK+ lymphomas may improve the prognosis.

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Acknowledgements

We especially acknowledge Dr Steve Morris for providing Karpas299, BaF3 and NPM-ALK transformed BaF3 cell lines and helpful comment for this manuscript. We also thank Dr Shile Huang for stimulating discussions. This study was supported by Program for New Century Excellent Talents in University (NCET-05-0788).

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Authors and Affiliations

  1. Laboratory of Hematology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China

    L Gu & Z Ma

  2. Laboratory of Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    L Gu

  3. Department of Pediatric Hematology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China

    J Gao, Q Li, Y P Zhu, C S Jia, R Y Fu, Y Chen, Q K Liao & Z Ma

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Correspondence to Z Ma.

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Gu, L., Gao, J., Li, Q. et al. Rapamycin reverses NPM-ALK-induced glucocorticoid resistance in lymphoid tumor cells by inhibiting mTOR signaling pathway, enhancing G1 cell cycle arrest and apoptosis. Leukemia 22, 2091–2096 (2008). https://doi.org/10.1038/leu.2008.204

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