Date of Award

Spring 2023

Project Type

Thesis

Program or Major

Biochemistry

Degree Name

Master of Science

First Advisor

Sherine Elsawa

Second Advisor

Xuanmao Chen

Third Advisor

Don Wojchowski

Abstract

Waldenström macroglobulinemia (WM) is a sub-type of non-Hodgkin lymphoma associated with excess secretion of immunoglobulin M (IgM) and the infiltration of the bone marrow by lymphoplasmacytic cells. There is a dynamic oxygen gradient consumption and diffusion in the tumor microenvironment, leading to regions of hypoxia (1-3% O2 concentration). GLI1, GLI2 and GLI3 are members of the family of Kruppel-like factors with highly conserved Zinc finger DNA-binding domains in mammalian cells. They signal trough the Hedgehog pathway which is a conserved pathway among species and is crucial in fundamental development processes and tissue homeostasis. They can also signal trough non-canonical pathways like MAPKKK/MEKK, PI3K/AKT/mTOR, TGF-β, PKC, DIRK family and TLR/TRIF. GLI expression during hypoxic conditions has not been investigated in WM. Cytokines are small proteins that are crucial in controlling the growth and activity of other immune/blood cells. In cancer, cytokines mediate key interactions between immune and non-immune cells in the tumor microenvironment. Here we study IL-2Rα and IL-6Rα expression on WM cells. We found that GLI1, GLI2, GLI3, CD25 and gp80 mRNA expression are induced under hypoxic conditions. GLI1 protein was increased under similar conditions. We found that hypoxia promotes cell viability but there was no change in IgM secretion. Preliminary results suggest that GLI1 is signaling trough Hedgehog pathway under hypoxia. Preliminary results show that GLI1 silencing inhibits CD25 expression, suggesting that this is a novel target of this transcription factor. Since there is no cure for this disease, by understanding the basic biology it is possible to identify new targets for therapeutic intervention. In this project, the role of the hypoxic environment in the biochemistry of WM cells is evident and we show how GLI1 influences cytokine receptors that are involved in tumor progression, making GLI1 a possible target for WM treatment.

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