Abstract

Childhood CRLF2 B-cell Acute Lymphoblastic Leukemia (CRLF2 B-ALL) is a high-risk form of leukemia that is associated with poor patient survival outcomes. CRLF2 B-ALL is five times more prevalent in Hispanic children than others and is associated with a higher rate of relapse, thus contributing significantly to childhood cancer health disparities. This disease occurs due to alterations of the CRLF2 gene, leading to overexpression of the CRLF2 protein- a component of the receptor signaling complex for the cytokine Thymic Stromal LymphoPoietin (TSLP) on the surface of B-ALL cells. TSLP has been shown to induce proliferation of human and mouse B-cell precursors via activation of the JAK-STAT5 and more recently the PI3K/AKT/mTOR pathways. However, the mechanisms by which TSLP-CRLF2 interactions contribute to high-risk leukemia have not been elucidated. Therefore the objective of our studies was to elucidate the TSLP-induced mechanisms that contribute to high-risk CRLF2 B-ALL and to evaluate promising drug candidates to target high-risk B-ALL. Based on literature findings and preliminary data, we hypothesized that TSLP contributes to CRLF2 B-ALL by increasing proliferation and/or survival of leukemia cells via regulation of genes downstream of CRLF2 pathway activation. This hypothesis was tested using experiments developed under the following specific aims:- Aim 1: Optimize the novel hTSLP+/- xenograft model for use in defining the role of TSLP in CRLF2 B-ALL; Aim 2: Identify TSLP-induced cellular and molecular mechanisms that contribute to CRLF2 B-ALL; Aim 3: Assess candidate drugs’ efficacy against high-risk B-ALL. Results from the studies conducted to address the specific aims show that 1) the hTSLP+/hTSLP- mouse model produces detectable levels of hTSLP, which activates CRLF2 and expands normal B-cells and activates the mTOR cell survival pathway in CRLF2 B-ALL cells in vivo; 2) cellular assays of apoptosis along with gene expression data demonstrate that TSLP regulates the expression of genes that promote cell death and survival of CRLF2 B-ALL cells in vivo and in vitro; 3) drug efficacy studies performed on high-risk leukemia cells using several drug candidates demonstrate that the Mcl-1 inhibitor MIM1 and the Novomedix drug series induced cell death in CRLF2 B-ALL and Nalm6 cells respectively. Taken together, the data provide evidence that TSLP regulates cell survival mechanisms in CRLF2 B-ALL cells and provides a rationale for the use of combination therapies that include drugs which target cell survival molecules and/or cellular functions regulated by TSLP.

LLU Discipline

Anatomy

Department

Basic Sciences

School

School of Medicine

First Advisor

Payne, Kimberly J.

Second Advisor

Dovat, Sinisa

Third Advisor

Kearns-Jonker, Mary

Fourth Advisor

Oberg, Kerby

Fifth Advisor

Soto-Wegner, Ubaldo

Sixth Advisor

Weldon, David J.

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2015

Date (Title Page)

6-2015

Language

English

Library of Congress/MESH Subject Headings

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cytokines; Receptor - Cytokine; Cell Line - Tumor; Bone Marrow Cells; Stromal Cells; Gene Rearrangement - B-Lymphocyte - Heavy Chain; Immunoglobulin Class Switching; Protein Kinase Inhibitors; Janus Kinases; Signal Transduction

Subject - Local

Hispanic Children; Rate of Relapse; Childhood Cancer Health Disparities; Thymic Stromal LymphoPoietin

Type

Dissertation

Page Count

172

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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