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dc.contributor.advisorMichelle Kelliher, Ph.D.
dc.contributor.authorCullion, Kathleen J.
dc.date2022-08-11T08:08:43.000
dc.date.accessioned2022-08-23T16:05:28Z
dc.date.available2022-08-23T16:05:28Z
dc.date.issued2009-09-04
dc.date.submitted2011-07-18
dc.identifier.doi10.13028/xy9r-3310
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31876
dc.description.abstractGain of function NOTCH1 mutations are common in both patients with T-ALL and in mouse models of the disease. Inhibiting the Notch pathway in T-ALL cell lines results in growth arrest and/or apoptosis in vitro, suggesting a requirement for Notch signaling in T-ALL. Therefore, we sought to examine the role of Notch1 signaling in both premalignancy and in the maintenance of leukemic growth. Using a murine model of T-ALL, in which expression of the Tal1 and Lmo2 oncogenes arrests thymocyte development, our preleukemic studies reveal that Notch1 mutations are early events that contribute to the clonal expansion of DN3 and DN4 progenitors. We also demonstrate that progenitors are maintained within the tumor and are enriched in leukemia-initiating cell (L-IC) activity, suggesting Notch1 may contribute to L-IC self-renewal. By studying the effects of Notch signaling in murine T-ALL cell lines, we also demonstrate that Notch1 promotes the proliferation and survival of leukemic blasts through regulation of Lef1 and the Akt/mTOR pathways. Given that T-ALL cell lines are dependent on Notch signaling in vitro, we investigated the effects of Notch inhibition in vivo. We provide evidence that Notch1 can be successfully targeted in vivo and that Notch inhibition, with γ-secretase inhibitors (GSIs), significantly extends the survival of leukemic mice. We also demonstrate that administration of GSIs in combination with rapamycin inhibits human T-ALL growth and extends survival in a mouse xenograft model. Given that NOTCH1 may be required to maintain both L-IC and bulk leukemic growth, targeting NOTCH1 may prove to be an efficacious targeted therapy for T-ALL patients with aberrant NOTCH1 activation.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectReceptor
dc.subjectNotch1
dc.subjectPrecursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subjectCancer Biology
dc.subjectGenetic Phenomena
dc.subjectHemic and Lymphatic Diseases
dc.subjectImmune System Diseases
dc.subjectNeoplasms
dc.subjectTherapeutics
dc.titleMechanisms of NOTCH1 Mediated Leukemogenesis: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1539&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/537
dc.legacy.embargo2011-04-29T00:00:00-07:00
dc.identifier.contextkey2103620
refterms.dateFOA2022-08-25T05:54:38Z
html.description.abstract<p>Gain of function <em>NOTCH1</em> mutations are common in both patients with T-ALL and in mouse models of the disease. Inhibiting the Notch pathway in T-ALL cell lines results in growth arrest and/or apoptosis <em>in vitro</em>, suggesting a requirement for Notch signaling in T-ALL. Therefore, we sought to examine the role of Notch1 signaling in both premalignancy and in the maintenance of leukemic growth. Using a murine model of T-ALL, in which expression of the <em>Tal1</em> and <em>Lmo2</em> oncogenes arrests thymocyte development, our preleukemic studies reveal that <em>Notch1</em> mutations are early events that contribute to the clonal expansion of DN3 and DN4 progenitors. We also demonstrate that progenitors are maintained within the tumor and are enriched in leukemia-initiating cell (L-IC) activity, suggesting <em>Notch1</em> may contribute to L-IC self-renewal. By studying the effects of Notch signaling in murine T-ALL cell lines, we also demonstrate that <em>Notch1</em> promotes the proliferation and survival of leukemic blasts through regulation of Lef1 and the Akt/mTOR pathways.</p> <p>Given that T-ALL cell lines are dependent on Notch signaling <em>in vitro</em>, we investigated the effects of Notch inhibition <em>in vivo</em>. We provide evidence that Notch1 can be successfully targeted <em>in vivo</em> and that Notch inhibition, with γ-secretase inhibitors (GSIs), significantly extends the survival of leukemic mice. We also demonstrate that administration of GSIs in combination with rapamycin inhibits human T-ALL growth and extends survival in a mouse xenograft model. Given that NOTCH1 may be required to maintain both L-IC and bulk leukemic growth, targeting NOTCH1 may prove to be an efficacious targeted therapy for T-ALL patients with aberrant NOTCH1 activation.</p>
dc.identifier.submissionpathgsbs_diss/537
dc.contributor.departmentMolecular, Cell and Cancer Biology
dc.description.thesisprogramCancer Biology


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