Date of Award

Spring 2019

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Richard Goodwin

Abstract

Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled proliferation of long-lived plasma cells (PCs) in the bone marrow (BM), which constitute at least 10% of BM cellularity. Normally, long-lived plasma cells make up less than 1% of BM cells. Plasma cells become neoplastic when a clonal PC population produces a monoclonal immunoglobulin protein. A diagnosis of monoclonal gammopathy of undetermined significance (MGUS) is made when there is an increase in monoclonal PCs within the BM, but less than 10%, and the patient does not present with end-organ damage, which is associated with active MM. Though not considered pathological at this stage, individuals with MGUS are at an increased risk for developing MM. There are several challenging aspects in treating MM including the high clonal heterogeneity of MM cells and its clinical repercussions, thus making the malignancy difficult to treat. Further heterogeneity is found in regard to disease onset, disease progression, therapeutic resistance, and subsequent patient relapse.

The purpose of this project is to investigate the microniche of PCs as they transition from premalignant to malignant myeloma cells in order to provide valuable insight which can be exploited to test current and novel therapeutic treatments. This project has demonstrated changes in the expression of fibronectin and morphological differences in plasma cells within core biopsies, which may support disease progression. Additionally, the purpose of this project is also to generate a long-term 3D in vitro culture models of MM using a high-throughput hydrogel platform. By using BM aspirates from MGUS and MM patients, results demonstrated that this 3D culturing system is capable of reproducing key features on long-lived PCs. Furthermore, these BM cultures maintained their abnormal phenotypes for at least five days of culture. This extended timeframe allows for better characterization of the mechanisms of action of current therapies and testing of emerging treatments for this incurable disease.

Rights

© 2019, Katrina A. Harmon

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