Miss Khalisha Malik

Research project: Analysis of altered DNA repair pathways in Chronic Myeloid Leukaemia quiescent stem cells: a role for Poly ADP Ribose Polymerase (PARP) inhibition

Abstract

Tyrosine Kinase Inhibitors (TKI) such as Imatinib have revolutionized the treatment of the once prognostically dismal Chronic Myeloid Leukaemia (CML). Although, TKI may confer remission in most patients, there is a sizeable minority of CML patients that are resistant to TKI. TKI insensitivity has been shown to be dependent on the presence of quiescent leukemic stem cells that develop mechanisms to circumvent TKI activity. In this project, we will determine the DNA damage and repair mechanisms of CML stem cells that allow for leukemic evolution and protection from TKI. Using DNA repair assays we will study the contribution of single stranded repair and double strand DNA repair of CML stem cells and CML cell lines in conditions that are reminiscent of the bone marrow niche e.g., low oxygen, low nutrient. We will also compare the repair capacities of CML stem cells vs mature progenitor cells. Finally, we will determine the potential DNA repair inhibitors such as Poly ADP Ribose Polymerase (PARP) inhibitors with TKI for the elimination of the leukaemia stem cell.  Findings from this study will offer broad implications for the use of dual synthetic lethality strategies for the treatment of other cancers in addition to leukaemia.