Characterizing drug resistance in hypoxia-adapted chronic myeloid leukaemia cells.

• Main Author: Muhammad Rauzan Rafman.
• Other Authors: School of Biological Sciences
• Format: Final Year Project
• Language: English
• Published: 2013
• Subjects: DRNTU::Science::Biological sciences::Microbiology::Drug Resistance
• Online Access: http://hdl.handle.net/10356/52743
• Institution: Nanyang Technological University

The development of tyrosine kinase inhibitors (TKI) has improved treatment of chronic myeloid leukaemia (CML) but resistance is observed in patients with advanced-stage CML. Second-generation TKIs overcome most resistance mechanisms but are ineffective against quiescent and hypoxic CML stem cells. Most studies done on hypoxia in leukaemia were short-term but long-term hypoxia-adapted (HA) cells are more identical to primary CML samples. Effects of chronic hypoxia on drug resistance in CML were analysed through protein profiles of untreated and treated normoxic, short- and long-term hypoxic CML cells. Results showed that short-term hypoxia induced resistance against dasatinib, and imatinib by itself or in combination with either rapamycin or ABT-199. HA cells were more resistant and ABT-199 overcame resistance induced by short term hypoxia but not by chronic hypoxia. The signalling pathways involved may be different for drug resistance in hypoxic and HA cells due to the different protein profiles. Imatinib resistance was also found to persist after 3-week reoxygenation. Stat5, Erk, p38, Bcl-2 and Bim were suggested to have involvement in inducing drug resistance in HA cells. These helps in understanding the signalling pathways affected in chronic hypoxia-induced drug resistance in CML hence providing drug targets which can overcome this resistance.