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Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.

Publication ,  Journal Article
Kurokawa, M; Ito, T; Yang, C-S; Zhao, C; Macintyre, AN; Rizzieri, DA; Rathmell, JC; Deininger, MW; Reya, T; Kornbluth, S
Published in: Proc Natl Acad Sci U S A
February 5, 2013

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 5, 2013

Volume

110

Issue

6

Start / End Page

2300 / 2305

Location

United States

Related Subject Headings

  • Transduction, Genetic
  • Recombinant Proteins
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Protein Engineering
  • Piperazines
  • Mice
  • Leukemia
  • K562 Cells
  • Imatinib Mesylate
 

Citation

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Kurokawa, M., Ito, T., Yang, C.-S., Zhao, C., Macintyre, A. N., Rizzieri, D. A., … Kornbluth, S. (2013). Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells. Proc Natl Acad Sci U S A, 110(6), 2300–2305. https://doi.org/10.1073/pnas.1206551110
Kurokawa, Manabu, Takahiro Ito, Chih-Sheng Yang, Chen Zhao, Andrew N. Macintyre, David A. Rizzieri, Jeffrey C. Rathmell, Michael W. Deininger, Tannishtha Reya, and Sally Kornbluth. “Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.Proc Natl Acad Sci U S A 110, no. 6 (February 5, 2013): 2300–2305. https://doi.org/10.1073/pnas.1206551110.
Kurokawa M, Ito T, Yang C-S, Zhao C, Macintyre AN, Rizzieri DA, et al. Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2300–5.
Kurokawa, Manabu, et al. “Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.Proc Natl Acad Sci U S A, vol. 110, no. 6, Feb. 2013, pp. 2300–05. Pubmed, doi:10.1073/pnas.1206551110.
Kurokawa M, Ito T, Yang C-S, Zhao C, Macintyre AN, Rizzieri DA, Rathmell JC, Deininger MW, Reya T, Kornbluth S. Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2300–2305.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 5, 2013

Volume

110

Issue

6

Start / End Page

2300 / 2305

Location

United States

Related Subject Headings

  • Transduction, Genetic
  • Recombinant Proteins
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Protein Engineering
  • Piperazines
  • Mice
  • Leukemia
  • K562 Cells
  • Imatinib Mesylate