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Current Biotechnology

Volume 1 Issue 2
ISSN: 2211-5501
eISSN: 2211-551X

 

   All Titles

  Targeting BCR-ABL Oncoprotein for Leukemia Therapy: Current Biotechnology and Future Perspectives
  pp.175-183 (9) Authors: Min Shen, Q. Ping Dou
doi: 10.2174/10175
 
 
      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
  Affiliation: Karmanos Cancer Institute, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit, MI 48201, USA.
 
  Key: New Content Free Content Open Access Plus Subscribed Content

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