Bcr-Abl-independent imatinib-resistant K562 cells show aberrant protein acetylation and increased sensitivity to histone deacetylase inhibitors

Bcr-Abl-independent signaling pathways are known to be in-volved in imatinib resistance in some patients with chronic myelogenous leukemia (CML). In this study, to find new targets for imatinib-resistant CML displaying loss of Bcr-Abl kinase target dependence, we isolated imatinib-resistant variants, K562/R1, K562/R2, and K562/R3, which showed profound de-clines of Bcr-Abl levels and its tyrosine kinase activity, from K562 cells. Importantly, the imatinib resistance mechanism in these variants also included aberrant acetylation of nonhistone proteins such as p53, Ku70, and Hsp90 that was due to up-regulation of histone deacetylases (HDACs) and down-regula-tion of histone acetyltransferase (HAT). In comparison with K562 cells, the imatinib-resistant variants showed up-regula-tion of HDAC1,-2, and-3 (class I HDACs) and class III SIRT