BCR-ABL in chronic myeloid leukaemia

 

BCR-ABL is an oncogene resulting from a chromosomal translocation found in 95% of CML [34], and in some acute myeloid and lymphoblastic leukaemias. The translocation between chromosomes 9 and 22 generates the Philadelphia chromosome, giving rise to a BCR-ABL fusion gene composed of exons 1-3 from BCR and all except the first exon from ABL [35]. The identification of this translocation in CML cells provided the first example of a chromosomal translocation in cancer [36], though it was not proven until later that it could induce tumorigenesis. When BCR-ABL was forcibly expressed in mouse models, development of several hematologic malignancies, particularly CML, was observed [37].

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Wild-type ABL is a highly regulated tyrosine kinase with roles in the cell cycle, genotoxic stress response and integrin signalling [38]. The fusion of BCR-ABL results in the loss of the ABL autoinhibition domain, and ultimately leads to its deregulation [39]. This constitutively active tyrosine kinase hyper-phosphorylates a vast range of substrates involved in growth, cell adhesion and inhibition of apoptosis, which results in the induction of tumorigenesis. The dependence of CML on BCR-ABL for survival was demonstrated through the clinical success of BCR-ABL inhibitors, most notably imatinib. Like gefitinib and erlotinib, imatinib is a small molecule tyrosine kinase inhibitor but has high specificity for BCR-ABL; it inhibits BCR-ABL by binding in the active site, locking the kinase in its autoinhibited conformation. The remarkable efficacy of imatinib in CML patients during clinical trials led to its rapid FDA approval to treat the disease in the USA [40]. However, it has since emerged that drug resistance can develop in CML patients that renders them unresponsive to imatinib treatment, typically through gene amplification of BCR-ABL or mutations in its catalytic domain [41].  Such drug resistance is especially prevalent during the later stages of CML, including the accelerated phase or blast crisis [42].