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The response to Histone deacetylase inhibitor in Imatinib resistant, BCR-ABL independent, K562 variant with high levels of phosphorylated P38

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Author(s): Esther Rabizadeh | Adina Aviram | Inessa Belyaev | Vita Mirkin | Yael Zimra

Journal: Journal of Hematological Malignancies
ISSN 1925-4024

Volume: 2;
Issue: 4;
Start page: 33;
Date: 2012;
Original page

Keywords: Imatinib-resistance | BCR-ABL | HDACI | K562

ABSTRACT
Background: Imatinib mesylate, a TK inhibitor, is the main treatment for chronic myelogenous leukemia (CML), but patients may develop drug resistance. Mutations within the Abl kinase domain, increased expression of BCR-ABL or other regulatory mechanisms were suggested to be involved. However, recently the importance of BCR-ABL independent mechanisms in Imatinib resistance has been suggested. Exploring the role of proteins involved in BCR-ABL independent resistance is of great importance in designing new modalities to overcome resistance or potentiate TKI efficacy. Cell model and Methods: In order to investigate the mechanisms of resistance, we developed an Imatinib resistant K562 cell line (K562-R). We focused on the involvement of BCR-ABL protein and p38 phosphorylation in K562-R resistance and the response to histone deacetylase inhibitor (HDACI). Cellular and molecular studies were conducted using flow cytometer, protein array, and RT-PCR and sequence analysis. Results: Continuous exposure of K562-S to Imatinib mesylate resulted in an emerging sub-clone resistant to the drug. The acquired resistance was found to be independent of BCR-ABL. K562-R exhibited elevated spontaneous apoptosis in correlation with elevated levels of phosphor-p38 and a significant decrease in the expression of Wilms' tumor (WT1). Interestingly, the extent of apoptosis induction by HDACI was significantly higher in K562-R than in K562-S cells. HDACI induced phosphorylation of p38 in both cells. Nevertheless, inhibition of phosphor-p38 by SB203510 did not affect the response to HDACI neither in K562-S nor in K562-R cells. Conclusions: Our data suggests that phospor-p38 do not play a major role in the apoptosis induced by this HDACI in K562-S and K562-R cells. However, the potentiated response of HDACI in K562-R cells may have an implication for combined therapy design in CML treatment. Further investigation on the role of proteins associated with apoptosis pathways may have important implications in future design of new modalities to overcome resistance or potentiate TKI efficacy.
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