Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.
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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.
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl
Hematopoietic Stem Cells
Protein Kinase Inhibitors
Published Version (Please cite this version)10.1073/pnas.1206551110
Publication InfoDeininger, MW; Ito, T; Kornbluth, S; Kurokawa, M; Macintyre, AN; Rathmell, Jeffrey C; ... Zhao, C (2013). Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells. Proc Natl Acad Sci U S A, 110(6). pp. 2300-2305. 10.1073/pnas.1206551110. Retrieved from https://hdl.handle.net/10161/8388.
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Jo Rae Wright University Professor
Our lab studies the regulation of complex cellular processes, including cell cycle progression and programmed cell death (apoptosis). These tightly orchestrated processes are critical for appropriate cell proliferation and cell death, and when they go awry can result in cancer and degenerative disorders. Within these larger fields, we have focused on understanding the cellular mechanisms that prevent the onset of mitosis prior to the completion of DNA replication, the process
Adjunct Associate Professor in the Department of Pharmacology and Cancer Biology
My laboratory studies the mechanisms and role of glucose metabolism in lymphocyte survival and activation. We have found that dramatic increases in glucose metabolism are necessary for lymphocytes to survive and mount immune responses. Excessive glucose metabolism, however, can lead to T cell hyperactivation and autoimmunity. A key mechanism for control of lymphocyte glucose metabolism is regulation of glucose uptake by the glucose transporter, Glut1. Interestingly, upregulation of Glut1
Adjunct Associate Professor in the Department of Pharmacology & Cancer Biology
All the cells of the blood are derived from the hematopoietic stem cell. This cell has the remarkable ability to self-renew as well as to differentiate into mature blood cells of all lineages. The primary goal of our lab is to elucidate the signaling pathways that regulate the choice between stem cell renewal and commitment. These studies have implications not only for understanding the basic mechanisms that regulate stem cell development and oncogenic renewal, but also for enhancing stem c
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Professor of Medicine
My research interests focus on the care of patients with hematologic malignancies, both with and without the use of bone marrow or stem cell transplantation. I focus my research efforts on new approaches to manipulate minimal residual disease.Recent endeavors have included: Phase one trials with novel anti-cancer agents targeting aurora kinases, tyrosine kinases, mtor, VEGF, and raf/ras pathways New monoclonal antibodies targeting tumor stroma rat
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