Targeting the MAP Kinase pathway in human acute myeloid leukemia cells using a recombinant anthrax lethal toxin. (c2013)

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dc.contributor.author Kassab, Elias
dc.date.accessioned 2013-09-03T09:57:47Z
dc.date.available 2013-09-03T09:57:47Z
dc.date.copyright 2013 en_US
dc.date.issued 2013-09-03
dc.date.submitted 2013-05-15
dc.identifier.uri http://hdl.handle.net/10725/1548
dc.description Includes bibliographical references (leaves 41-44). en_US
dc.description.abstract In this study, we attempt to target the mitogen-activated protein kinase (MAPK) pathway in acute myeloid leukemia (AML) cells using a recombinant anthrax lethal toxin (LeTx). Around 15,000 new case of Acute Myeloid Leukemia are diagnosed each year with a fatality rate of 65%. The poor prognosis rate is due to the high proliferative and quick progressive characteristics of AML. However, most AML patients eventually relapse due to persistence of chemotherapy-resistant blasts in the bone marrow hence the need for alternative approaches employing novel, more selective mechanisms for targeting AML blasts. One such approach consists of targeting the mitogen-activated protein (MAP) kinase (MAPK) pathway in AML cells. LeTx consists of protective antigen (PrAg) and lethal factor (LF). PrAg binds cells, is cleaved by furin, oligomerizes, binds three to four molecules of LF, and undergoes endocytosis, releasing LF into the cytosol. LF cleaves MAPK kinases, inhibiting the MAPK pathway. The MAKP pathway is a conserved pathway between eukaryotes. Through a wide range of extracellular signals, the MAPK pathway regulates growth, proliferation, differentiation and death. Its constitutive activation, particularly the Ras/Raf/MEK1/2/ERK1/2 cascade promotes proliferation and survival of most human cancer cells. We tested potency of LeTx on a panel of 11 human AML cell lines. Seven cell lines showed cytotoxic responses to LeTx. Cytotoxicity of LeTx was mimicked by the specific mitogen-activated protein/extracellular signal–regulated kinase kinase 1/2 (MEK1/2) inhibitor U0126, indicating that LeTx-induced cell death is mediated through the MEK1/2–extracellular signal–regulated kinase (ERK1/2) branch of the MAPK pathway. The four LeTx-resistant cell lines were sensitive to the phosphatidylinositol 3-kinase inhibitor LY294002. Flow cytometry analysis of MAPK pathway activation revealed presence of phospho-ERK1/2 only in LeTx-sensitive cells. In this study, we have shown that a majority of AML cell lines are sensitive to the LF-mediated inhibition of the MAPK pathway. Furthermore, we have demonstrated that LeTx-induced cytotoxicity in AML cells is non-apoptotic and dependent on phospho-ERK1/2 levels. en_US
dc.language.iso en en_US
dc.subject Acute myeloid leukemia -- Pathogensis en_US
dc.subject Mitogen-activated protein kinases en_US
dc.subject Blood -- Diseases -- Molecular aspects en_US
dc.subject Cancer -- Molecular aspects en_US
dc.subject Lebanese American University -- Dissertations en_US
dc.subject Dissertations, Academic en_US
dc.title Targeting the MAP Kinase pathway in human acute myeloid leukemia cells using a recombinant anthrax lethal toxin. (c2013) en_US
dc.type Thesis en_US
dc.term.submitted Spring en_US
dc.author.degree MS in Molecular Biology en_US
dc.author.school Arts and Sciences en_US
dc.author.idnumber 200600671 en_US
dc.author.commembers Dr. Roy Khalaf
dc.author.commembers Dr. Mirvat El-Sibai
dc.author.woa OA en_US
dc.description.physdesc 1 bound copy: xv, 44 leaves; ill. (chiefly col.); 31 cm. Available at RNL. en_US
dc.author.division Biology en_US
dc.author.advisor Dr. Ralph Abi Habib
dc.keywords Mitogen-Activated Protein Kinase en_US
dc.keywords Acute Myeloid Leukemia en_US
dc.keywords Anthrax Lethal Toxin en_US
dc.keywords ERK1/2 en_US
dc.keywords MEK1/2 en_US
dc.keywords Cytotoxicity en_US
dc.keywords Flow Cytometry en_US
dc.keywords Western Blot en_US
dc.identifier.doi https://doi.org/10.26756/th.2013.13 en_US
dc.publisher.institution Lebanese American University en_US

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