Chronic myeloid leukemia is a disorder of hematopoietic stem cells caused by the expression of BCR-ABL. Loss of p53 has not been implicated as important for the development of CML. Mutations in p53 protein are infrequent however correlate with the disease progression. The absence of p53 mutations does not exclude the possibility that other dysfunctions play an important role in CML pathology. Acetylation represents a very potent posttranslational mechanism regulating p53 stability, transcriptional activity and localization. In this study we showed that expression of BCR-ABL could cause the high acetylation level of p53, specifically at lysine 317/320 (K317/K320), which has been shown to regulate nuclear export and transcription-independent apoptotic activity of p53. We found that BCR-ABL expression increases K317 acetylation of p53 and is able to prevent acetylation drop observed upon DNA damage, followed by translocation of p53 to the cytoplasm and Bax activation. We showed that this site plays a crucial role in the regulation of p53 localization and p53-dependent, Bax mediated apoptosis. Our study presents a novel BCR-ABL-dependent mechanism protecting from DNA-damage-induced cell death. It can, in addition to already known mechanisms, explain the resistance to p53-dependent apoptosis observed in CML cells expressing wt p53.
Supported by grant 2P04A 05729 from the Ministry of Science and Higher Education in Poland