MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27KIP1 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-06-18

AUTHORS

M T Gómez-Casares, E García-Alegria, C E López-Jorge, N Ferrándiz, R Blanco, S Alvarez, J P Vaqué, G Bretones, J M Caraballo, P Sánchez-Bailón, M D Delgado, J Martín-Perez, J C Cigudosa, J León

ABSTRACT

Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and dasatinib. In the CML-derived K562 cell line, low concentrations of imatinib induce proliferative arrest and erythroid differentiation. We found that imatinib upregulated the cell cycle inhibitor p27KIP1 (p27) in a time- and -concentration dependent manner, and that the extent of imatinib-mediated differentiation was severely decreased in cells with depleted p27. MYC (c-Myc) is a transcription factor frequently deregulated in human cancer. MYC is overexpressed in untreated CML and is associated to poor response to imatinib. Using K562 sublines with conditional MYC expression (induced by Zn2+ or activated by 4-hydroxy-tamoxifen) we show that MYC prevented the erythroid differentiation induced by imatinib and dasatinib. The differentiation inhibition is not due to increased proliferation of MYC-expressing clones or enhanced apoptosis of differentiated cells. As p27 overexpression is reported to induce erythroid differentiation in K562, we explored the effect of MYC on imatinib-dependent induction of p27. We show that MYC abrogated the imatinib-induced upregulation of p27 concomitantly with the differentiation inhibition, suggesting that MYC inhibits differentiation by antagonizing the imatinib-mediated upregulation of p27. This effect occurs mainly by p27 protein destabilization. This was in part due to MYC-dependent induction of SKP2, a component of the ubiquitin ligase complex that targets p27 for degradation. The results suggest that, although MYC deregulation does not directly confer resistance to imatinib, it might be a factor that contributes to progression of CML through the inhibition of differentiation. More... »

PAGES

2239-2246

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2012.246

DOI

http://dx.doi.org/10.1038/onc.2012.246

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1018679426

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22710719


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