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Title: MicroRNA control of drug-resistance in haematological malignancies
Authors: Screen, Michael P.
Supervisors: Willis, Anne
MacFarlane, Marion
Award date: 1-Apr-2015
Presented at: University of Leicester
Abstract: miRNAs have been shown to play a role in fundamental cellular processes. They are also involved in drug-resistance mechanisms, which hamper the treatment of many types of cancer, including haematological malignancies. This study sought to uncover mechanisms of miRNA-induced drug-resistance in two haematological malignancies: diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). To this end, profiling of DLBCL and MM-derived cell lines was carried out to identify miRNAs whose levels were altered relative to their respective controls. The expression levels of these miRNAs were then modulated in the cell lines to examine the effect upon cell survival. The miRNA profiling data of the DLBCL cell lines compared to their control “normal” B-cell lines, was then combined with the results of previously performed “translational profiling” in which levels of mRNA translation are compared. Translational profiling identified upregulation of certain DNA damage repair (including BRCA2) and anti-apoptotic (including Bcl-2) proteins in the DLBCL cell lines. Importantly, the miRNA profiling data identified downregulation of miR-34a and miR-146 in the DLBCL cell lines, which are reported to target Bcl-2 and BRCA2, respectively. In GCB-DLBCL patient samples low miR-34a expression correlated with poor prognosis. In MM, the miRNA profile of an acquired multidrug-resistant cell line (8226/R5) was compared with the profile of its parental sensitive cell line and the miR-200 family was identified as upregulated in the resistant line. Overexpression of miR-200b, miR-200c or miR-429 in the parental cell line increased resistance to the proteasome inhibitor bortezomib. The increased resistance was due to direct targeting of the pro-apoptotic protein, Noxa, by the miR-200bc/429 family. Acquired bortezomib-resistant cell lines, which were only resistant to proteasome inhibitors, were then generated. miR-200b was again upregulated in these new cell lines, suggesting that increased expression of the miR-200bc/429 family is a possible mechanism for acquired bortezomib-resistance in MM.
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author. All rights reserved.
Description: The file associated with this record is under embargo for 1 year.
Appears in Collections:Theses, MRC Toxicology Unit
Leicester Theses

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