Current Biotechnology

Pabulo Henrique Rampelotto  
Center of Biotechnology and PPGBCM
Federal University of Rio Grande do Sul
Porto Alegre, RS
Brazil

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Targeting BCR-ABL Oncoprotein for Leukemia Therapy: Current Biotechnology and Future Perspectives

Author(s): Min Shen, Q. Ping Dou.

Abstract:

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 kinase inhibitor.

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Article Details

VOLUME: 1
ISSUE: 2
Year: 2012
Page: [175 - 183]
Pages: 9
DOI: 10.2174/2211550111201020175
Price: $58