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APL

Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells

A Corrigendum to this article was published on 24 January 2005

Abstract

Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-AsR), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-AsR cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-AsR than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-AsR. These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.

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Acknowledgements

This paper has been supported by grants from the ‘Associazione Italiana per la Ricerca sul Cancro’ (AIRC) from the ‘Ministero dell’Istruzione dell’Università e della Ricerca Scientifica’ (MIUR): FIN, FIL and ‘Progetto Strategico Oncologia SP/4: Terapia preclinica molecolare in oncologia’ and from ‘Associazione Chiara Tassoni per la Lotta contro la Leucemia e il Cancro-Parma’.

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Lunghi, P., Tabilio, A., Lo-Coco, F. et al. Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells. Leukemia 19, 234–244 (2005). https://doi.org/10.1038/sj.leu.2403585

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