Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Biology

Supervisor

Alexander Timoshenko

Abstract

Galectins are a family of β-galactoside binding proteins with roles in cellular differentiation, apoptosis, and cancer progression. To better understand this important class of proteins, HL-60 acute myeloid leukemia cells were used as a model for comparative study of the effects of recombinant galectins, galectin inhibitors, and all-trans retinoic acid (ATRA) on granulocytic differentiation. Targeted inhibition of galectin-1 or -3 induced characteristics of neutrophilic differentiation including segmentation of nuclei, upregulation of neutrophil cytosolic factor 1 gene expression, and a global decrease in protein glycosylation with O-linked N-acetylglucosamine. Recombinant galectin-8 or -9 also induced granulocytic differentiation that was not observed with recombinant galectin-1 or -3. However, the galectin induced differentiation was moderate relative to the strong stimulatory effects observed with ATRA. In silico analysis of acute myeloid leukemia data from the Cancer Genome Atlas revealed changes in galectin gene expression profiles related to the various molecular subtypes of acute myeloid leukemia. A ratio of galectin-12/galectin-9 gene expression was identified as a potential diagnostic marker of leukemia subtypes. Correlation analysis between galectin gene pairs revealed changes to the glycobiological landscape and relation to granulocytic differentiation markers in leukemia cells. Among galectin genes, only the increased galectin-1 gene expression was indicative of patient poor prognosis in all acute myeloid leukemia cohorts. These results indicate that while galectins share similar structures, they elicit different responses and display different gene expression patterns in relation to granulocytic differentiation in acute myeloid leukemia. Furthermore, these findings suggest the possible utility of galectins as targets for differential therapeutics.

Summary for Lay Audience

Galectins are a group of sugar binding proteins involved with the immune system and cancer. Acute myeloid leukemia (AML) is a fast-acting cancer of the blood and bone marrow. Patients with AML have weaker immune systems and lower immune cell counts because of a larger number of cancer cells. To date, the treatments for AML include chemotherapy and many drugs including all-trans retinoic acid (ATRA). AML poses issues in treatment and diagnosis due to the wide range of genetic changes that occur within the cancer cells. In this study, different galectins in HL-60 cells (an AML cancer cell line) were used to see how these proteins influence the cell development of the immune system for possible new targets in AML therapies. In HL-60 cells, the inhibition of galectin-1 or galectin-3 as well as the supplementary addition of galectin-8 or galectin-9 resulted in an increase in developed immune cells. However, all galectin responses were weaker when compared to ATRA treated cells. Galectins were also investigated to find new diagnostic and prognostic markers of AML. When comparing galectins between healthy and cancer cells, galectin-9 and galectin-12 showed changes specific to cancer cells, serving as a new diagnostic marker. Additionally, increased expression of galectins-1, -4 and -10 all serve as new prognostic markers in AML. Overall, my findings revealed that galectins are related to the development of the immune system and serve as new diagnostic and prognostic markers. This suggests that galectins might prove useful as potential new targets for AML therapies.

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