The Mutational, Environmental and Immunological Drivers of Leukemia Resistance Pubblico

Abstract

The therapeutic resistance of leukemia is shaped by mutational, environmental, and immunological drivers. Acute Lymphoblastic leukemia (ALL) is the most common malignancy in children and adolescents, accounting for 30% of all childhood cancers. B-cell Acute Lymphoblastic Leukemia (B-ALL) is the most common hematological malignancy found in children. Hematological neoplasms comprise a heterogeneous group of malignant disorders of the blood and bone marrow and are the most common childhood cancers. Deleterious alterations to DNA, also known as mutations, are the causative event behind these malignancies. In 2014, a patient presented with the first known case of leukemia harboring the SEPT9-ABL1 oncogenic fusion gene, showing resistance to tyrosine kinase inhibition. Obesity, which is a nationwide healthcare crisis, also contributes to survival outcomes in leukemia. Studies conducted by the Dr. Henry and Dr. Porter Laboratories have previously explored the relationship between the adipocyte microenvironment and the chemotherapy resistance in leukemia cells. There is data to suggest that since cancer cell phenotypes are distinct from cells of normal physiological function, they can initiate an innate immune response. Therefore, my work between the Dr. Henry and Dr. Porter Laboratories has entailed 1. exploring the impact of the SEPT9f-ABL1 mutation on leukemia oncogenicity and treatment responses, 2. studying the interplay between the adipocyte secretome and chemoresistance in leukemia and 3. investigating non-specific T-Cell killing mechanisms in

leukemia. In Vitro cell proliferation assays suggest that SEPT9f-ABL1 expression induces interleukin-3 independence in leukemia cell lines and correlates with downstream activation of pro-proliferative pathways. The simultaneous exploration of the adipocyte secretome from a single-cell transcriptomic as well as a proteomic standpoint revealed an adipocyte-induced increase in metabolic signatures associated with chemoresistance in both in vitro and in B-ALL patient samples. Lastly, T-cell killing Assays support cross-protective non-specific T-cell killing mechanisms in leukemia. 

Table of Contents

TABLE OF CONTENTS

SECTION I: How Does Mutation Impact Leukemia Cell Proliferation and Treatment

Responses?

Introduction...................................................................................................1

Materials and Methods .......................................................................................6

Results.........................................................................................................9

Discussion And Future Directions........................................................................10

SECTION II: Environmental Drivers Of B-ALL

Introduction.....................................................................................................12

Materials and Methods .......................................................................................14

Results..........................................................................................................14

Discussion And Future Directions..........................................................................16

SECTION III: Understanding Immunogenicity Towards B-ALL

Introduction.....................................................................................................18

Materials and Methods ........................................................................................20

Results..........................................................................................................22

Discussion And Future Directions..........................................................................23

SECTION IV: FIGURES

Figure 1: The Structure of the Philadelphia Chromosome..............................................24

Figure 2: IC-50 Curves for Imatinib, Dasatinib, Asciminib and

Ponatinib in BaF3-MSCV-p190................................................. ..........................25

Figure 3: Scheme for the Generation of SEPT9-ABL1 in pWPI Vector.............................26

Figure 4: The SEPT9f-ABL1 protein isoform is expressed,

accompanied by downstream CRKL phosphorylation.................................................27

Figure 5: SEPT9f-ABL1expression induces IL-3 Independence in BaF3..........................28

Figure 6: High Fat High Sucrose Diet impairs normal B-cell function, reduces the frequency of B-cell populations, and downregulates gene programs associated with positive B-ALL outcomes in murine adipose tissue.....................................................................................29

Figure 7: The plasma of lean pediatric patients with B-ALL is exclusively characterized by the presence of heat shock proteins, cytoskeletal proteins, and proteins that promote cardiovascular health...........................................................................................................30

Figure 8: Adipocytes secrete metabolites which may promote the growth of cancer cells........31

Figure 9: Adipocyte-secreted factors statistically significantly upregulate proteins associated with glutaminolysis, b-oxidation, B-progenitor cell development, and chemoresistance in the absence and presence of chemotherapy treatment.......................................................32

Figure 10: CD19 and CD95L Surface Ligand is stably expressed at high levels on B-ALL Cells............................................................................................................33

Figure 11: Jurkat T-Cells Recognize and Induce Apoptosis in Human B-ALL cells in a Non- Antigen Specific Manner....................................................................................34

SECTION V: REFRENCES..............................................................................35 

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Molecular Health Sciences, Oncology
Parola chiave	cancer immunology tyrosine kinase inhibition BCR-ABL1 leukemia drug resistance chemoresistance T-PLL SEPT9-ABL1 B-ALL
Committee Chair / Thesis Advisor	Antonio Brathwaite, Emory University
Committee Members	Miyoung Lee, Emory University Christopher Porter, Emory University Dailia Francis, Emory University

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