Targeting translation factors in haematologic malignancies.

• Main Author: Lee, Janice Siu Hui.
• Other Authors: School of Biological Sciences
• Format: Final Year Project
• Language: English
• Published: 2011
• Subjects: DRNTU::Science::Biological sciences
• Online Access: http://hdl.handle.net/10356/44751
• Institution: Nanyang Technological University

Imatinib resistance arose in patients with chronic myeloid leukaemia (CML) due to the alterations in the BCR-ABL kinase domain. It was established that the elevated β-catenin activation led to the progression of CML from chronic phase to blast crisis phase. Inhibition of phosphorylated eIF4E (p-eIF4E) was found to avert the activation of β-catenin. The goals of this project were to establish the relationship between p-eIF4E and β-catenin activation, to contrast the effects of drugs sorafenib and imatinib in reducing the amount of β-catenin activation and to investigate if the inhibitory effects of sorafenib on p-eIF4E were specifically via the inhibition of Mnk 1/2. Effects of drug treatments on K562 and HL-60 cell lines were analysed using western blots, TOP-flash assays and immunofluorescence assays. Unlike imatinib, sorafenib was able to inhibit the p-eIF4E (P value<0.05). A positive correlation was found between p-eIF4E and β-catenin activation (P value<0.05). Compared to imatinib, 10μM of sorafenib was able to significantly reduce the amount of β-catenin activation via the inhibition of p-eIF4E (P value <0.005). Sorafenib not only acts as an alternative for imatinib, it might significantly reduce the β-catenin activation specifically found in leukemic stem cells, preventing the progression of CML and other haematologic malignancies.