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You searched for +publisher:"University of North Carolina" +contributor:("Zimmerman, Eric"). One record found.

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University of North Carolina

1. Zimmerman, Eric. MOLECULAR ADAPTATION TO ANTI-CANCER CHEMOTHERAPY IN LEUKEMIA.

Degree: Pharmacology, 2011, University of North Carolina

Drug resistance to anti-cancer chemotherapy is a significant barrier to the treatment of leukemia patients. Many times, resistance results from molecular adaptation to drug exposure, such as genetic mutation of key enzymes, up-regulation of pro-survival compensatory signaling pathways, and altered drug transport. In this dissertation, we describe two examples of molecular drug resistance in cell models of 1) Ara-C-resistant acute lymphoblastic leukemia (ALL) and 2) imatinib-resistant chronic myelogenous leukemia (CML). First, we determined that nucleoside transport is deficient in the Ara-C-resistant T-cell ALL CCRF-CEM cell line (Ara-C/8C) in comparison to drug-sensitive parental CCRF-CEM cells. Further study found a single point mutation in glycine residue 24 (G24) within equilibrative nucleoside transporter 1 (ENT1), a protein responsible for nucleoside uptake in these cells. Therefore, we tested the ability of G24A, G24R, and G24E ENT1 mutants to transport uridine and Ara-C and localize to the plasma membrane. Our data suggest that mutation of G24 disrupts ENT1 transport activity without altering localization; thus, expression of mutant ENT1 may confer Ara-C resistance in CCRF-CEM AraC/8C cells. In the second portion of the dissertation, we studied the role of Lyn tyrosine kinase (Lyn) in imatinib-resistant CML MYL-R cells. In comparison to drug-sensitive parental MYL cells, Lyn was hyper-active, and loss of Lyn activity sensitized cells to imatinib treatment. We determined that Lyn inhibited miR181 microRNA (miRNA) expression in MYL-R cells at the transcriptional level. In addition, we determined that miR181b targeted the 3' UTR of Mcl-1, a pro-survival protein associated with drug-resistance, resulting in Mcl-1 degradation. Thus, we defined a molecular signaling axis by which Lyn may confer drug resistance in imatinib-resistant CML. We attempted to elucidate the mechanism of Lyn-dependent miR181 expression and found that 1) the transcription factors CREB and STAT5 do not regulate miR181a/b and 2) Lyn may regulate miR181c/d expression through modification of histone acetylation. These studies contribute to our knowledge of drug resistance mechanisms in leukemia and provide novel biomarkers for the identification of drug-resistant cancer. Advisors/Committee Members: Zimmerman, Eric, Graves, Lee, Nicholas, Robert, Johnson, Gary, Hammond, Scott, Lawrence, David.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Zimmerman, E. (2011). MOLECULAR ADAPTATION TO ANTI-CANCER CHEMOTHERAPY IN LEUKEMIA. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:ff100956-ccba-4659-b349-99bda9a325d6

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Zimmerman, Eric. “MOLECULAR ADAPTATION TO ANTI-CANCER CHEMOTHERAPY IN LEUKEMIA.” 2011. Thesis, University of North Carolina. Accessed October 28, 2020. https://cdr.lib.unc.edu/record/uuid:ff100956-ccba-4659-b349-99bda9a325d6.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Zimmerman, Eric. “MOLECULAR ADAPTATION TO ANTI-CANCER CHEMOTHERAPY IN LEUKEMIA.” 2011. Web. 28 Oct 2020.

Vancouver:

Zimmerman E. MOLECULAR ADAPTATION TO ANTI-CANCER CHEMOTHERAPY IN LEUKEMIA. [Internet] [Thesis]. University of North Carolina; 2011. [cited 2020 Oct 28]. Available from: https://cdr.lib.unc.edu/record/uuid:ff100956-ccba-4659-b349-99bda9a325d6.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Zimmerman E. MOLECULAR ADAPTATION TO ANTI-CANCER CHEMOTHERAPY IN LEUKEMIA. [Thesis]. University of North Carolina; 2011. Available from: https://cdr.lib.unc.edu/record/uuid:ff100956-ccba-4659-b349-99bda9a325d6

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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