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Sensitivity and Resistance to Therapy

Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

Abstract

A cytokine-dependent (FL5.12), drug-sensitive, p53 wild type (WT) and a doxorubicin-resistant derivative line (FL/Doxo) were used to determine the mechanisms that could result in drug resistance of early hematopoietic precursor cells. Drug resistance was associated with decreased p53 induction after doxorubicin treatment, which was due to a higher level of proteasomal degradation of p53. Dominant-negative (DN) p53 genes increased the resistance to chemotherapeutic drugs, MDM-2 and MEK inhibitors, further substantiating the role of p53 in therapeutic sensitivity. The involvement of signal transduction and apoptotic pathways was examined, as drug resistance did not appear to be due to increased drug efflux. Drug-resistant FL/Doxo cells had higher levels of activated Raf/MEK/ERK signaling and decreased induction of apoptosis when cultured in the presence of doxorubicin than drug-sensitive FL5.12 cells. Introduction of DN MEK1 increased drug sensitivity, whereas constitutively active (CA) MEK1 or conditionally active BRAF augmented resistance, documenting the importance of the Raf/MEK/ERK pathway in drug resistance. MEK inhibitors synergized with chemotherapeutic drugs to reduce the IC50. Thus the p53 and Raf/MEK/ERK pathways play key roles in drug sensitivity. Targeting these pathways may be effective in certain drug-resistant leukemias that are WT at p53.

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Acknowledgements

JAM, SLA and LSS have been supported in part by a grant from the NIH (R01098195). JB has been supported in part from a grant from the Deutsche Krebshilfe (1061250). AMM was supported in part from grants from the CARISBO Foundation and from Progetti Strategici UNIBO EF2006. FN was supported in part by the grant PRIN from Ministero dell'Istruzione, dell'Università e della Ricerca. ML was supported in part by a grant from Lega Italiana per la Lotta contro i Tumori. We appreciate the assistance in qRT-PCR provided by Dr. Nicholas Polakowski.

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McCubrey, J., Abrams, S., Ligresti, G. et al. Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance. Leukemia 22, 2080–2090 (2008). https://doi.org/10.1038/leu.2008.207

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