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Molecular Targets for Therapy

MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM

Leukemia volume 23, pages 1744–1754 (2009)Cite this article

Abstract

Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. We and others have shown that BIM (BCL-2 interacting mediator of cell death), a BH3-only pro-apoptotic protein, is up-regulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia (ALL) cells and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation. We therefore hypothesized co-treatment with Dex and MEK/ERK inhibitors would promote apoptosis in ALL cells through BIM up-regulation and activation. We show here that MEK inhibitors (PD184352 and PD98059) synergistically enhance Dex lethality in a variety of ALL cells and in two primary ALL specimens. Co-treatment with Dex and PD184352 results in BIM accumulation, pro-apoptotic BAX/BAK activation, and cytochrome c release from mitochondria. Down-regulation of BIM by short-hairpin RNA (shRNA) in ALL cells suppressed BAX/BAK activation, cytochrome c release, and cell death by Dex/PD184352 co-treatment. BIM accumulated by this treatment sequesters anti-apoptotic BCL-XLMCL-1, resulting in the release of BAK from these anti-apoptotic molecules. This study provides a rational foundation for future attempts to improve the activity of GCs with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematologic malignancies.

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Acknowledgements

We thank members of Dr Grant's lab for valuable advice and discussion. This work was supported by the Leukemia Research Foundation (to HH) and NIH RO1CA100866 (to SG).

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  1. A A Rambal and Z L G Panaguiton: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    A A Rambal, Z L G Panaguiton, L Kramer, S Grant & H Harada

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  1. A A Rambal
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Correspondence to H Harada.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Rambal, A., Panaguiton, Z., Kramer, L. et al. MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM. Leukemia 23, 1744–1754 (2009). https://doi.org/10.1038/leu.2009.80

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