The chimeric oncoprotein BCR-ABL, resulting from Philadelphia (Ph) chromosome translocation, is crucial for
the pathogenesis of chronic myelogenous leukemia (CML) as well as a subset of acute lymphoblastic leukemia (ALL).
Due to the loss of regulatory motifs during the fusion process, BCR-ABL has constitutive tyrosine kinase activity that is
critical for oncogenesis. This provides the rationale for developing drugs that specifically inhibit BCR-ABL tyrosine
kinase activity. The first tyrosine kinase inhibitor (TKI), imatinib mesylate (STI571, Gleevec®), was launched in 2001,
completely changing the landscape of therapy for CML. However, imatinib-resistant cases emerged in the clinic, most
caused by mutations in the BCR-ABL tyrosine kinase domain or BCR-ABL gene amplification. This urged the
development of next-generation TKIs that can override imatinib-resistance. Instead of inhibiting tyrosine kinase activity,
an alternative strategy, currently being tested in clinical trials, is to induce BCR-ABL degradation by heat shock protein
90 inhibitors or proteasome inhibitors. A more tentative strategy is to entrap BCR-ABL in the nucleus based on the
finding that nuclear BCR-ABL is pro-apoptotic. Moreover, the unique mRNA and amino acid sequences at the junctional
region of BCR-ABL provide an opportunity for specific targeting by gene therapy and immunotherapy, respectively.
Therefore, a deep understanding of the biology of BCR-ABL in the context of CML and the use of state-of-the-art
biotechnology have aided and will continue to aid in the development of targeted therapy for BCR-ABL-driven leukemia
and minimal residue disease (MRD).
Keywords: Antisense therapy, ALL, BCR-ABL, CML, HSP90 inhibitor, imatinib, imatinib-resistance, leukemia vaccine,
minimal residual disease, nuclear entrapment, proteasome inhibitor, ribozyme, RNA interference, T315I mutation, tyrosine
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