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Chronic myeloid leukaemia (CML) is a cancer of the hematopoietic system that arises from the Philadelphia chromosome (Ph1). This results from the reciprocal translocation of chromosomes 9 and 22 which generates a Bcr-Abl fusion gene encoding a 210kDa protein with constitutive tyrosine kinase activity (Ben-Neriah et al., 1986; Kuzrock et al., 1988). This constitutively active tyrosine kinase drives proliferation and survival through multiple downstream pathways (Reviewed in Cowan-Jacob et al., 2004; Ren et al., 2005). The disease is characterised by three stages; the chronic phase marked by an accumulation of mature granulocytes and myeloid precursors in the bone marrow and peripheral blood; the accelerated phase characterised by a rise in myeloid precursors and a blast crisis stage which is characterised by a marked accumulation of differentiation-arrested blast cells of either myeloid or lymphoid lineage (Calabretta & Perotti, 2004; Savage et al., 1997). The generation and clinical use of the Bcr-Abl tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) has revolutionised the treatment of CML patients (Druker et al., 1996; Druker et al., 2006) and has become the standard line of therapy for CML patients. Following treatment with imatinib, over 90% of patients obtain a complete haematologic response and more than 80% achieve a complete cytogenetic response. However, there are limitations associated with IM therapy. The drug is highly effective in the chronic phase of the disease but the response of patients in blast crisis is limited (Hehlman & Saussele, 2008). Furthermore, in approximately 40% of patients, resistance develops i.e. resistance in 100 patient years (Gorre et al., 2001). Great progress has been made over the last ten years in elucidating the molecular mechanisms of IM-resistance in vitro but correlating any of these individual resistance mechanisms in a clinical sample does not always indicate that it alone drives clinical progression as additional modes of resistance may be at work. The mechanisms by which patients become resistant to IM therapy include Bcr-Abl dependent mechanisms such as an increase in the levels of Bcr-Abl mRNA expression and corresponding upregulation of protein levels and amplification of the Bcr-Abl gene (Mahon et al. 2000). Bcr-Abl independent mechanisms include activation of signalling pathways downstream of Bcr-Abl including the phosphatidylinositol 3-kinase (PI3K)/Akt cell survival pathway or activation of signalling pathways separate to that of the Bcr-Abl gene and an efflux of IM via multidrug resistant proteins such as p-glycoprotein (Capdeville et al., 2002). The most well-characterised cooperating pathway involves the Src Family Kinases (SFKs) which have

Treatment of Chronic Myeloid Leukaemia: Current Practice and Future Prospects