Elucidating the Role of Soluble Galectin-9 in B-cell Acute Lymphoblastic Leukemia Pathogenesis Open Access
Ank, Raira (Summer 2021)
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
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