Date of Award

Spring 2025

Project Type

Thesis

Program or Major

Biochemistry

Degree Name

Master of Science

First Advisor

Sherine Elsawa

Second Advisor

Victoria Jeffers

Third Advisor

Sarah Walker

Abstract

Waldenström Macroglobulinemia (WM) is an incurable subtype of non-Hodgkin’s lymphoma characterized by high levels of circulating serum IgM and bone marrow infiltration by malignant cells. As in other hematological malignancies, the tumor microenvironment (TME) is crucial for tumorigenesis and survival of WM cells. The TME is composed by non-cancer cells, including stromal and endothelial cells, immune cells, and adipocytes, metabolites, lymphatic and blood vessels, extracellular matrix, and signaling components, such as chemokines, cytokines and growth factors. Bone marrow stromal cells (BMSCs) are essential for hematopoiesis, since they secrete stromal factors and cytokines, including Interleukin (IL)-6. IL-6 modulates the secretion of IgM by WM cells, contributing to cancer-associated symptoms. The Bromodomain and extra-terminal (BET) proteins are epigenetic modulators that play a role in numerous cellular processes including cell proliferation, cell survival, cell cycle, and cell differentiation. BET proteins are key to transcription initiation and elongation. They bind to acetylated lysine residues of the histone tails and recruit several transcription factors, leading to initiation of transcription. BET proteins modulate different signaling pathways, including the Hedgehog (Hh) signaling pathway. GLI2, one of the transcription factors activated by the Hh pathway, is involved in the secretion of IL-6 by BMSC and this was shown to modulate WM biology. The goal of this research was to examine the effect of BET inhibitors on BMSC biology.

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