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Protein Arginine Methyltransferase 5 as a Driver of Lymphomagenesis

Smith, Porsha L
http://rave.ohiolink.edu/etdc/view?acc_num=osu1468975682

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Over the past decade, it has become clear that oncogenesis is a process driven by a wide variety of triggers including gene mutations, gene amplifications, inflammation, and immune deficiency. The growing pool of data collected from whole genome and epigenome studies of both solid and blood cancers has pointed toward dysregulation of chromatin remodelers as a unique class of cancer drivers. Next generation sequencing studies of lymphomas have identified a wide array of somatic mutations affecting enzymes that regulate epigenetic control of gene expression. Lymphoma is a type of cancer that originates in secondary lymphoid organs and manifests as an outgrowth of transformed lymphocytes, or white blood cells (WBCs) in the blood. The majority of lymphoma cases can be grouped into the Non-Hodgkin’s lymphoma (NHL) subset and mainly occurs in B-cells. B-cell NHL is a heterogeneous set of cancers that would benefit from new therapies to improve patient progression-free survival. Cancers such as NHL typically present with a combination of genetic and epigenetic aberrations that contribute to the malignancy program. The epigenetic modifier protein arginine methyltransferase 5 (PRMT5) is required for B-cell transformation following Epstein-Barr virus (EBV) infection, and is overexpressed in various subsets of B-cell NHL. Based on these data we hypothesized that PRMT5 is a major driver of B-cell lymphomagenesis. To explore the role of PRMT5 in the development and progression of B-cell NHL we created a small molecule inhibitors targeted to PRMT5. Using the NHL subset mantle cell lymphoma (MCL) as a model we tested the efficacy of the drug. We discovered that PRMT5 was overexpressed in MCL primary samples and cell lines as compared to normal resting B cells. Furthermore, use of the small molecule inhibitor decreased the proliferation and viability in these cells without affecting the normal B-cells. Additionally, use of inhibitors caused G2/M cell cycle and decreased the expression of the oncogenic cell cycle proteins cyclin D1, CDK4 and c-myc but de-repressed the expression of the tumor suppressors PDCD4, C/EBPß and ST7. Finally, Nanostring analysis confirmed the dysregulation of multiple microRNA pathways which is attenuated with PRMT5 inhibition. To further explore the role of PRMT5 as a potential driver of lymphomagenesis, we created an Eµ-PRMT5 mouse model that overexpressed human PRMT5 in the B-lymphoid compartment of FVB/N mice. Using this model we demonstrated an increase in the incidence of lymphoma as compared to non-transgenic mice. Most of the lymphomas developed were pre-B-cell however the model also generated a number of T-cell lymphomas. Indeed we were also able to isolate and propagate the Tg813 T-cell lymphoma cell line from a transgenic mouse tumor. Inhibition of PRMT5 in the Tg813 cell line with a small molecule inhibitor resulted in apoptosis and loss of the expression of the oncogenic proteins cyclin D1 and c-myc. Furthermore, engraftment of the 813 cell line into both SCID and FVB/N mice caused disseminated lymphoma, characterized by organomegaly and lymphoid tumors, and was lethal within 21 days post-engraftment. Genetic editing utilizing CRISPR/CAS9 technology and an inducible guide RNA system illustrated that genetic knockout of PRMT5 in this line led to decreased proliferation. Taken together, these data demonstrate the role of PRMT5 as a lymphoma driver and describe a novel class of inhibitors in MCL as well as the first PRMT5 transgenic mouse model.
Robert Baiocchi (Advisor)
David Lucas (Committee Member)
Gregory Lesinski (Committee Member)
Deepa Sampath (Committee Member)
224 p.
Biology; Biomedical Research; Cellular Biology; Experiments; Health Sciences; Molecular Biology
protein arginine methyltransferase 5; PRMT5; epigenetics; transgenic; cancer; lymphomagenesis; cancer driver; lymphoma; lymphoma mouse model;

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Citations

  • Smith, P. L. (2016). Protein Arginine Methyltransferase 5 as a Driver of Lymphomagenesis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468975682

    APA Style (7th edition)

  • Smith, Porsha. Protein Arginine Methyltransferase 5 as a Driver of Lymphomagenesis. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1468975682.

    MLA Style (8th edition)

  • Smith, Porsha. "Protein Arginine Methyltransferase 5 as a Driver of Lymphomagenesis." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468975682

    Chicago Manual of Style (17th edition)

osu1468975682
1,251
© 2016, some rights reserved.Creative Commons License Protein Arginine Methyltransferase 5 as a Driver of Lymphomagenesis by Porsha L Smith is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.