Elucidating the Role of Soluble Galectin-9 in B-cell Acute Lymphoblastic Leukemia Pathogenesis Open Access

Abstract

Hematological malignancies, including B-cell acute lymphoblastic leukemia (B-ALL), represent the largest class of cancers in pediatric patients. Risk factors, including obesity, have been shown to significantly decrease survival outcomes as much as 30%.   This observation is alarming given The Center for Disease Control and Prevention (CDC) prediction that 20% of children ages 2-19 in the United States are obese with these numbers predicted to double within the next decade. These observations emphasize the need to further understand the relationship between obesity, leukemia development, and therapeutic responses.

We demonstrate that adipocyte-secreted factors promote B-ALL pathogenesis in a Galectin-9 (Gal-9)-dependent manner. Galectin-9 is a tandem repeat type member of the galectin family which has a wide range of biological functions, including inducing cellular proliferation, promoting apoptosis, and enhancing immune escape of malignant cells. In its soluble form, Gal-9 suppresses T-cell activation at low concentrations and is cytotoxic to T-cells at high concentrations. Mass spectrometry profiling of adipocyte-conditioned media (ACM) revealed the presence of several proteases, including thrombin, which has a cleavage site in the Gal-9 linker region.

Given the role of Gal-9 in immunosuppression, and that adipocyte-secreted factors cleave Gal-9 from the surface of B-ALL cells, I hypothesize that adipocyte-secreted thrombin cleaves Gal-9 from the surface of B-ALL cells which promotes B-ALL immune evasion. 

Table of Contents

Introduction and Background Information

Acute Lymphoblastic Leukemia  1

Clinical Presentation of B-ALL   1

Current Treatments for B-ALL   2

Childhood Leukemia and Obesity   3

Obesity and Immunity  4

Obesity and Cancer Immunotherapies  7

T-cell Mediated Immunity and Galectin-9     8

Summary Models  10

Scope of Thesis  11

 

Materials and Methods                                                                                          

Murine T-cell Activation Assay    12  

Human T-cell Activation Assay  12

Mass Spectrometry Analysis 12

Soluble Gal-9 Detection via ELISA   13

Diet-Induced Obesity Mouse Model  13

Blinatumomab-Induced T-cell Cytotoxicity Assay 13  

Results 

Adipocyte-secreted factors attenuate primary murine T-cell function 14

T-cell function is attenuated in obese patients without leukemia compared to healthy weight peers     15                         

Proteases identified through mass spectrometry analysis of adipocyte-conditioned media    16

Adipocyte-secreted factors increase soluble Gal-9 levels   16

Human recombinant thrombin cleaves Gal-9 from human B-ALL cells 17

Obesity potentiates B-ALL development    17

Adipocyte-conditioned media reduces blinatumomab-induced CD8⁺ T-cell mediated cytotoxicity      18

Recombinant Gal-9 treatment attenuates murine T-cell activation  19

 

Discussion    19

References   22

About this Master's Thesis

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Cancer Biology
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Oncology Health Sciences, Immunology
Keyword	cancer biology leukemia
Committee Chair / Thesis Advisor	Henry, Curtis J., Emory University
Committee Members	Shanmugam, Mala, Emory University Lesinski, Greg, Emory University

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