Date of Award

12-1-2016

Degree Type

Thesis

Degree Name

Master of Science

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Stephen O. Mathew

Second Advisor

Porunelloor A. Mathew

Third Advisor

W. Paul Bowman

Abstract

Acute lymphoblastic leukemia (ALL) is a cancer that mainly affects children around the age of five. Due to current treatments, 80-90% of children achieve long-term remission. However, because of the current treatments, which include chemotherapy and CNS-directed radiation, these children may experience late effects which impact growth and development. Even though survival rate is high, quality of life can be greatly reduced for some of the survivors. Natural Killer (NK) cells are cells of the innate immune system that are important in fighting cancer and virally-infected cells. They have been a subject of interest in ALL because ALL of the B cell lineage is particularly resistant to NK cell killing. NK cells get activated by their surface receptors and their ligands on target cells. In B cell ALL, the NK cells do not appear to get the proper activating signals and this has been determined to be one reason this cancer is able to thrive. Our lab has cloned three immune receptors, 2B4 (CD244), CS1 (CRACC, CD319) and LLT1 (CLEC2D), that are expressed on NK cells as well as other immune cells. These receptors have been shown to play an important role in NK cell activation. Two other receptors, NKp30 and NKp46, are well-known activating receptors that have also been implicated in ALL. In this project I compared the mRNA and surface protein receptor expression of immune receptors between healthy subjects and ALL subjects. Altered expression of immune receptors was observed in ALL subjects. In particular, a significant decrease in mRNA expression of 2B4, LLT1 and NKp30 was observed in ALL subjects at diagnosis compared to healthy subjects. mRNA expression of CS1 was increased significantly after chemotherapy treatment. In contrast, NKp46 mRNA expression was significantly increased in ALL subjects as compared to healthy subjects. Cell surface protein expression of CS1 was significantly upregulated on T cells and monocytes and LLT1 on NK cells of ALL subjects at diagnosis. Interestingly, NKp30 was overexpressed on B cells, T cells, monocytes and NKp46 was overexpressed on T cells and monocytes but not on NK cells of ALL subjects at diagnosis. I also detected a significant increase of soluble CS1and BAT-3 in ALL subjects at diagnosis between the ages of 1-11 yrs. Also, soluble CD48 was significantly increased in ALL subjects after chemotherapy treatments. Future mechanistic studies may shed more light in the immune dysfunction in ALL ultimately contributing to better treatment options for patients with pediatric ALL.

Comments

Powers, Sheila B., Expression and Function of Immune Receptors in Pediatric Acute Lymphoblastic Leukemia. Master of Science (Biomedical Sciences), November, 2016.

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