Item – Theses Canada

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OCLC number
1033041027
Link(s) to full text
LAC copy
LAC copy
Author
Wong, Peggy.
Title
Molecular Pathogenesis of T Lymphoblastic Lymphomas in an Atm-deficient Mouse Model.
Degree
(PhD)--University of Toronto, 2013.
Publisher
Toronto : University of Toronto, 2013.
Description
1 online resource
Notes
Includes bibliographical references.
Abstract
T lymphoblastic lymphoma/leukemia (T-LL) represent malignant disease of T-cell progenitors. Dysregulation of Notch1 and IL-7R pathways promotes T-LL, however the timing of these events remains unclear. Furthermore, the spectrum of Notch1 mutations has not been fully characterized in T-LL models. Chapter 2 demonstrated 3 T-LLs classified based on activated Notch1 (ICN1) expression that arose spontaneously in mice lacking ataxia telangiectasia mutated (ATM) protein. One group expressed truncated forms of ICN1 (T-ICN1) resulting from frame-shifting PEST mutations. T-LL cells but not normal thymocytes expressed a proteoglycan, syndecan 1 (SDC1). SDC1+ blasts were detected in thymi with normal cellularity from clinically healthy mice, thus representing the earliest discernible stage of T-LL progression. T-ICN1 and IL-7R[alpha] were both aberrantly expressed at this early T-LL stage. Therefore, these data suggest that Notch1 mutations, aberrant expression of IL-7R[alpha] and SDC1 arise early during T-LL progression. Chapter 3 demonstrated a paucity of HD mutations, yet T-LL cells proliferated in a Notch ligand-independent fashion. Analysis of ICN1+ T-LLs revealed truncated Notch1 mRNAs lacking ligand-binding domain and part of negative regulatory region. All truncated transcripts contained the intramembranous methionine that has previously been shown to serve as the translational start site. Collectively, our data identify truncated Notch1 mRNAs in T-LLs that likely encode for polypeptides undergoing ligand-independent activation. The third group lacked ICN1 expression (UD-ICN1). Chapter 4 revealed that UD-ICN1 T-LLs expressed low levels of Notch targets and proliferated independently of Notch signal. Gene set enrichment analyses of genes differentially expressed between UD-ICN1 and T-ICN1 T-LLs revealed higher levels of transcription factor krüppel-like factor 9 (Klf9) and other transcriptional regulators associated with the highly proliferative pre-DP stage of normal T-cell development. siRNA knockdown experiments demonstrated that Klf9 promoted proliferation of UD-ICN1 T-LL cells. Although further studies are warranted, the findings in this thesis reveal oncogenic activation of Notch1 as an early event in Atm-/- T-LL progression, and truncated Notch1 transcripts likely represent a novel mode of ligand-independent Notch1 activation. On the other hand, Klf9 promotes proliferation of Notch-independent T-LLs and may represent a potential therapeutic target for this T-LL group.
Other link(s)
tspace.library.utoronto.ca
hdl.handle.net
Subject
T lymphoblastic lymphoma and leukemia.
Notch1 mutations.
Klf9.
Microarray.
Gene expression profiles.
Notch1 deletions.