Converting an oncogenic protein into an apoptotic factor: targeting BCR-ABL to the mitochondria

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Title Converting an oncogenic protein into an apoptotic factor: targeting BCR-ABL to the mitochondria
Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Constance, Jonathan Eric
Date 2013-05
Description The advent of rational drug design to target a single molecular event, as so aptly demonstrated with tyrosine kinase inhibitor (TKI) therapy and Bcr-Abl, has set a precedent for the ability to attack malignancy directly at the level of the oncogenic event. However, in the last decade it has become clear that new therapeutic strategies for chronic myelogenous leukemia (CML) must move beyond the mere inhibition of Bcr-Abl's tyrosine kinase activity if a cure is to be found. TKI resistance, persistent leukemic stem cells, and the acute blast phase crisis remain major problems to be solved. This work describes the efforts to use the central leukemogenic protein of CML, Bcr-Abl (oncogenic event itself), to selectively destroy the diseased cells that harbor it. The subcellular localization of Bcr-Abl determines its function. This is also true for Bcr-Abl's normal counterpart, c-Abl. When localized to the mitochondria, c-Abl is a potent inducer of cell death. However, c-Abl pro-death activity is disrupted in CML. The mitochondriolytic mechanism of ‘death-directed' c-Abl is unknown. Yet, under conditions of cell stress from a variety of sources (e.g., endoplasmic reticulum stress, genotoxic agents, and oxidative stress) active c-Abl migrates to the mitochondria causing dysfunction and cell death. Our direct targeting of c-Abl and Bcr-Abl to the mitochondria demonstrated the sufficiency of c-Abl alone to kill leukemia cells and of Bcr-Abl's ability to recapitulate this function. iv The central hypothesis of this study is that forcing Bcr-Abl to the mitochondria will selectively induce the death of leukemic cells by converting Bcr-Abl into an apoptotic factor. This approach restores a defunct apoptotic pathway (i.e., the mitochondrial ‘death-directed' c-Abl pathway) and does not rely on the indirect engagement of (often dysregulated) cell death mechanisms like many chemotherapeutics. c-Abl requires a mitochondrial chaperone (protein kinase Cδ). Therefore, we designed a protein chaperone, the intracellular cryptic escort (iCE), for Bcr-Abl that selectively functions in the pro-oxidative environment of CML cells. Though, the iCE did not move Bcr-Abl to the mitochondria, it did synergistically and selectively kill CML cells as a combination with imatinib or alone was as toxic as high dose imatinib.
Type Text
Publisher University of Utah
Subject Leukemia - Treatment - Molecular aspects; Leukemia - Genetic aspects; Mitochondrial pathology
Subject MESH Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Mitochondrial Membrane Transport Proteins; Apoptosis Regulatory Proteins; Drug Design; Molecular Targeted Therapy; Molecular Chaperones
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Converting an Oncogenic Protein into an Apoptotic Factor: Targeting BCR-ABL to the Mitochondia. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections.
Rights Management Copyright © Jonathan Eric Constance 2013
Format application/pdf
Format Medium application/pdf
Format Extent 11,727,706 bytes
Source Original in Marriott Library Special Collections, RC39.5 2013.C66
ARK ark:/87278/s6g76nvm
Setname ir_etd
ID 196294
Reference URL https://collections.lib.utah.edu/ark:/87278/s6g76nvm
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