GSBS Dissertations and Theses

Publication Date

2013-05-10

Document Type

Doctoral Dissertation

Academic Program

Cancer Biology

Department

Molecular, Cell and Cancer Biology Department

First Thesis Advisor

Michelle Kelliher, PhD

Keywords

Notch1 Receptor, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, myc Genes

Subjects

Dissertations, UMMS; Receptor, Notch1; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Genes, myc

Abstract

Although cure rates have significantly improved for children with T-cell acute lymphoblastic leukemia (T-ALL), 20-30% undergo induction failure or relapse with most succumbing to disease. Leukemia-initiating cells (L-ICs) are hypothesized to be resistant to conventional chemotherapy and radiation and are thereby responsible for disease recurrence. Using an in vivo limiting dilution assay, we previously showed that the murine T-ALL L-IC is quite rare, with only 0.003-0.05% of cells capable of initiating disease, and demonstrated that the L-IC is a subset of the leukemic DN3 thymic progenitor population. Work described in this thesis validates the L-IC assay using two transplantation methods to rule out effects of homing and/or microenvironment on T-ALL L-IC survival and maintenance. Using this assay, we demonstrate that sustained Notch1 signaling is required for T-ALL initiation in vivo and show that treatment with a Notch1 inhibitor reduces or in some cases eliminates the L-IC population. We further analyze the effects of inhibiting c-Myc, a Notch1-regulated gene, on L-IC frequency and uncover an essential role for c-Myc in L-IC survival and expansion. Suppressing c-Myc by using specific shRNAs or a c-Myc inhibitor reduces the L-IC population and interferes with leukemia initiation. Together, these findings reveal a critical role of the Notch1-c-Myc pathway in T-ALL initiation and suggest that therapeutics targeted at this pathway could be used to treat and/or prevent disease relapse in patients.

DOI

10.13028/M2NC8V

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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