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

Abstract

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1073/pnas.1206551110

Publication Info

Kurokawa, Manabu, Takahiro Ito, Chih-Sheng Yang, Chen Zhao, Andrew N Macintyre, David A Rizzieri, Jeffrey C Rathmell, Michael W Deininger, et al. (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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Scholars@Duke

Macintyre

Andrew Neil Macintyre

Associate Professor in Medicine

Andrew Macintyre, PhD, directs the Immunology Unit within the Duke Regional Biocontainment Laboratory. The Macintyre lab team designs and performs assays to quantify immune reconstitution and immune responses. The lab specializes in multiplex cytokine arrays, flow cytometry, high-throughput ELISAs, qRT-PCR, and other molecular tests. 

The assays his team develops and runs support research into biodefense and critical public health challenges. Long-running collaborative projects include the evaluation of radiation countermeasures and the development of vaccines for influenza, gonorrhea, SARS-CoV2, and other pathogens.

Rizzieri

David Alan Rizzieri

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:

  1. Phase one trials with novel anti-cancer agents targeting aurora kinases, tyrosine kinases, mtor, VEGF, and raf/ras pathways 
  2. New monoclonal antibodies targeting tumor stroma rather than cellular antigens 
  3. Investigating new antibody targets, i.e. CD123, endoglin, or tenascin for hematologic malignancies 
  4. Aggressive therapy and transplantation for mantle cell lymphoma 
  5. Antiangiogenesis therapy for patients with NHL 
  6. Nonablative allogeneic transplantation therapy with matched or mismatched donors followed by immune modulation
Rathmell

Jeffrey Charles Rathmell

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 and glucose metabolism has also long been observed in cancer cells of all varieties and this may play an important role in cancer cell growth and survival. It remains unknown, however, how Glut1 expression or localization is regulated and how alterations in glucose uptake may affect immunity or cancer. To address this issue we are taking three approaches.

(1) Determine the signal transduction mechanisms that regulate Glut1 expression and intracellular trafficking.
(2) We have generated Glut1 transgenic mice that express Glut1 specifically in T cells and are making a conditional Glut1 knockout mouse to study the role of glucose uptake in T cell activation and regulation of Bcl-2 family proteins.
(3) We are also addressing how alterations in glucose uptake may affect development of cancer and if leukemias may become “metabolically addicted” to high glucose metabolism.

Our approach of studying the mechanism and role of metabolic regulation in lymphocytes bridges immunology and metabolism research. Ultimately, understanding this problem may lead to new metabolic approaches to immune and cancer therapies.


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