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THE ROLE OF SURVIVIN IN DRUG RESISTANT
PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
by
Eugene Park
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
August 2010
Copyright 2010 Eugene Park
Object Description
| Title | The role of survivin in drug resistant pediatric acute lymphoblastic leukemia |
| Author | Park, Eugene |
| Author email | eupark@chla.usc.edu; eugenehpark@gmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2010-06-30 |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-08-04 |
| Advisor (committee chair) |
Kahn, Michael Kim, Yong-Mi |
| Advisor (committee member) |
Müschen, Markus Tokes, Zoltan |
| Abstract | Despite the recent advances in chemotherapy for acute lymphoblastic leukemia (ALL), drug resistance resulting in relapse and long-term side effects of current treatments warrant new treatment modalities. Survivin/BIRC5, an inhibitor of apoptosis (IAP) protein, is critical for the survival and proliferation of cancerous cells and has become the target of an increasing number of preclinical novel therapies against primarily solid tumors. Survivin is expressed in AML and ALL cells and has been implicated in leukemia relapse. We test the hypothesis that survivin is critical to the pathway of self-renewal and maintenance of drug resistant ALL cells. To address this hypothesis, we have developed a murine xenograft model of patient-derived ALL cells, which are referred to here as primary ALL cells, allowing us to assess novel therapies targeting survivin using non-invasive monitoring of leukemogenesis by bioluminescent imaging. Our data suggest that overexpression of survivin increases self-renewal and drug-resistance of patient-derived ALL cells in vitro and accelerates leukemogenesis in vivo. In addition, in vitro inhibition of survivin using shRNA strongly synergizes with conventional chemotherapy in patient-derived ALL cells and decreases self-renewal. In vivo inhibition of survivin prolongs survival of mice engrafted with drug resistant leukemia. Taken together, we show that survivin is a key component in drug-resistance and stem cell self-renewal of drug resistant ALL cells. |
| Keyword | survivin; BIRC5; acute lymphoblastic; leukemia; IAP |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3273 |
| Contributing entity | University of Southern California |
| Rights | Park, Eugene |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Park-3682 |
| Archival file | uscthesesreloadpub_Volume32/etd-Park-3682.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | THE ROLE OF SURVIVIN IN DRUG RESISTANT PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA by Eugene Park A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOCHEMISTRY AND MOLECULAR BIOLOGY) August 2010 Copyright 2010 Eugene Park |
