The Bcr-abl Oncogene As A Therapeutic Target

Chronic Myeloid Leukaemia (CML), is a clonal myeloproliferative disease categorised into three phases: chronic phase (CP), accelerated phase (AP) and blast crisis (BC). CML is characterised by the presence of the Philadelphia chromosome (PhC), found in over 90% of patients. The PhC is formed through a balanced reciprocal translocation between chromosome (q) 9q and 22q, generating the BCR-ABL fusion oncogene. The fusion encodes a chimeric BCR-ABL1 oncoprotein eliciting constitutively active tyrosine kinase (TK) activity, phosphorylating downstream cellular substrates which impact cellular proliferation, adhesion and apoptosis. Several studies have implicated the BCR-ABL1 oncoprotein TK activity as a substantial driver in CML pathogenesis, identifying it as a potential therapeutic target. Development of Tyrosine Kinase Inhibitor (TKI) Imatinib through extensive preclinical and clinical trials has led to its approval by the Food and Drug Administration (FDA) as first-line treatment for CML. Imatinib has provided a progression-free survival rate of 89% in CML patients, eliciting greater remission rates than pre-existing traditional combinatory therapy (interferon alpha (IFN &) therapy). Emerging Imatinib resistance has been combatted using second-line therapies such as Dasatinib and additional third-line therapy Ponatinib. Further development of novel therapies targeting BCR-ABL levels and its downstream signalling pathways will improve future anticancer therapies.