MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis

MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis

Bibliographic Details
Main Author: Kohnken, Rebecca
Language:English
Published: The Ohio State University / OhioLINK 2017
Subjects:
Biomedical Research
Cutaneous T cell lymphoma
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1511355292134921
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1511355292134921
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Biomedical Research
Cutaneous T cell lymphoma
spellingShingle Biomedical Research
Cutaneous T cell lymphoma
Kohnken, Rebecca
MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis
author Kohnken, Rebecca
author_facet Kohnken, Rebecca
author_sort Kohnken, Rebecca
title MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis
title_short MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis
title_full MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis
title_fullStr MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis
title_full_unstemmed MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis
title_sort micrornas in cutaneous t-cell lymphoma pathogenesis
publisher The Ohio State University / OhioLINK
publishDate 2017
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1511355292134921
work_keys_str_mv AT kohnkenrebecca micrornasincutaneoustcelllymphomapathogenesis
_version_ 1719453131137351680
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15113552921349212021-08-03T07:04:45Z MicroRNAs in Cutaneous T-cell Lymphoma Pathogenesis Kohnken, Rebecca Biomedical Research Cutaneous T cell lymphoma Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin’s lymphoma that is characterized by mature CD4+ T-cells that home to and proliferate within the skin. In the majority of patients, the disease eventually progresses to involve the blood and viscera. This is a heterogenous and complex cancer, and there are few effective therapies available for patients with advanced-stage disease. A hallmark of CTCL progression is epigenetic dysregulation, particularly involving abnormal expression of microRNAs (miRs). Novel therapeutic compounds with some promise in CTCL are epigenetic modifying drugs, such as histone deacetylase inhibitors (HDACi). However, despite initial responses in some patients, many will eventually relapse or develop clinical resistance. This failure highlights the urgent need for better understanding of the underlying pathogenesis of CTCL progression as well as identification of novel therapeutic targets. Therefore, we hypothesized that miRs play a central role in the pathogenesis of CTCL, by acting as both oncogenic and tumor suppressive factors, and that therapeutic targeting of miRs may represent an effective treatment strategy for CTCL patients. The first part of this thesis investigates an oncogenic miR, miR-181, in CTCL patient-derived cell lines as well as in primary CTCL patient cells. Previous work from our lab had shown decreased expression of sterile alpha motif (SAM) and histidine/aspartic acid (HD) domain-containing protein 1 (SAMHD1) in CTCL patients. SAMHD1 is a deoxynucleoside triphosphate hydrolase with established roles in nucleic acid metabolism, restriction of human immunodeficiency virus -1 replication, regulation of innate immune signaling, and modulation of DNA damage signaling. Recently, this gene has been implicated as a tumor suppressor gene in several types of cancer. The regulation of SAMHD1 and its potential role in the pathogenesis of CTCL was not previously known. We discovered that SAMHD1 protein levels were consistently and significantly decreased in CTCL patient-derived cell lines and primary patient cells. We were able to demonstrate regulation of SAMHD1 protein level by miR-181, a miR that was consistently upregulated in these samples. This work expanded on a novel means of regulating SAMHD1 expression in CD4+ T-cells and further implicated miR-181 dysregulation in the pathogenesis of CTCL. In the second portion of this thesis, we investigated an epigenetic miR, miR-29b, in CTCL patient-derived cell lines, primary patient cells, and a novel mouse model of CTCL. Previous work in our lab had shown suppression of miR-29b in interleukin-15 (IL-15)-driven large granular lymphocyte leukemia. We identify a novel target of miR-29b, a bromodomain and extra-terminal motif (BET) protein, bromodomain-containing protein 4 (BRD4). We elaborated on a regulatory pathway by which IL-15 signaling results in decreased miR-29b expression. This repression allows increased BRD4 chromatin binding across the genome, which results in increased oncogene expression in CTCL patient cells. Using the IL-15 transgenic mouse as a preclinical model of CTCL, we show that directly targeting BRD4 binding or indirect inhibition of BRD4 through rescue of miR-29b expression, results in decreased clinical disease severity. This work therefore identifies a novel regulatory loop in CTCL and provides insight into potential therapeutic targets to guide development of more effective treatment strategies for CTCL patients. Lastly, another oncogenic miR, miR-214, was investigated as a therapeutic target in CTCL. Previous work to describe the miR-nome of CTCL patients had identified miR-214 as upregulated in CTCL patients, a dysregulation that correlated with poor clinical outcome. We describe the epigenetic mechanism that upregulates miR-214 expression in CD4+ T-cells. Furthermore, we utilized the IL-15 transgenic mouse model of CTCL to evaluate the clinical efficacy of targeting miR-214 in vivo with an antagomiR-214. This work represents one of the first successful uses of antagomiR therapy in CTCL and provides further support to the notion of using miR-based therapies in this disease. This thesis addresses the complex epigenetic dysregulation critical to the development and progression of a rare form of lymphoma. These studies demonstrate the wide-ranging and varied function of miRs in CTCL, and provide mechanistic insight into regulation of miR expression as well as their downstream effects. Further, we provide preclinical data to support the development of miR-based therapies for CTCL patients, which may provide more effective and safer therapeutic options in the future. 2017 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1511355292134921 http://rave.ohiolink.edu/etdc/view?acc_num=osu1511355292134921 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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