A Study of the Impact of the Obese Microenvironment on Human Leukemia Cells Público

Abstract

Cancer research has seen a dramatic increase in the number of deaths relating to obesity. Adipocytes have been thought to be drivers of cancers such as leukemia, although the exact mechanism by which they confer resistance to chemotherapy drugs and promote tumor formation is unknown. A previous study by Sheng et. alindicates that adipocytes secrete some sort of protective factor that prevents apoptosis in acute lymphoblastic leukemia (ALL) cells. The primary goal of this project is to uncover the various pathways by which adipocytes confer resistance and promote leukemogenesisin order to improve upon treatment for both obese and lean patients. This was done by looking at cell death, cell proliferation, and gene expression profiles of various T-ALL and B-ALL cell lines. While the data provided ample evidence for how adipocytes impact the survival and proliferation of leukemia cells, future studies must be done to quantify gene expression specific to certain pathways. Targeting such pathways will allow for more effective and localized chemotherapy drugs and treatments.

Table of Contents

Introduction                                                                                                                                     1

Results and Discussion                                                                                                                   6

Conclusions                                                                                                                                  16

Future Directions                                                                                                                          17

Experimental                                                                                                                                 19

References                                                                                                                                     22

Figures, Tables, and Schemes:

Figure 1: sPLS-DA plot of the top 10 differentially expressed proteins present upon exposure to ACM, SCM, and DMEM 6

Figure 2: EdU data of KOPN8 cells in RPMI, SCM, and ACM. Representation of KOPN8 and REH leukemia cells in various mitotic stages 8

Figure 3: Annexin-V data of KOPN8 cell death in conditioned medias alone and with MTX, cell death and apoptosis levels in both KOPN8 and REH cell lines in conditioned media alone and with MTX 10

Figure 4: Principal Component Analysis plots for KOPN8 and REH cells conditioned in ACM, SCM, and RPMI both with and without MTX 12

Figure 5: Structures of nonfluorescent and acetylated forms of DCF        17                  

Figure 6: “Boronate-based” switch of MitoPY1 upon oxidation with hydrogen peroxide 18

Table 1: Upregulated and downregulated genes present in chemosensitive B-ALL cells upon exposure to adipocyte conditioned media (ACM) 13

Table 2: Upregulated and downregulated genes present in chemoresistant B-ALL cells upon exposure to adipocyte conditioned media (ACM) 14

Table 3: Upregulated and downregulated genes present in chemosensitive B-ALL cells upon exposure to adipocyte conditioned media (ACM) and methotrexate (MTX) 14

Table 4: Upregulated and downregulated genes present in chemoresistant  B-ALL cells upon exposure to adipocyte conditioned media (ACM) and methotrexate (MTX) 15

Scheme 1: Adipocyte-produced leptin promotes hematopoiesis and leukemogenesis 4

Scheme 2: General experimental procedures for cells in ACM, SCM and RPMI both with and without MTX 19

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.A.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Biochemistry Biology, Cell Health Sciences, Immunology
Palavra-chave	Obesity leukemia
Committee Chair / Thesis Advisor	Dr. Curtis Henry, Emory University
Committee Members	Michael McCormick, Emory University Brenda Harmon, Emory University

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