Graduate Date

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Dr. Runqing Lu

Second Advisor

Dr. Shantaram S. Joshi

Abstract

Chronic Lymphocytic Leukemia (CLL) represents the most common adult leukemia in the Western hemisphere. Despite considerable progress in our current understanding of CLL, this disease remains incurable and the molecular events underlying the complex pathogenesis of CLL are not fully elucidated. Interferon Regulatory Factor 4 (IRF4) belongs to the IRF superfamily of transcription factors that has been shown to play critical roles at multiple stages of B cell development. Interestingly, a Genome Wide Association Study identified Single Nucleotide Polymorphism (SNP) mediated IRF4 down regulation, as a major predisposing genetic event during the development of CLL. However, whether low levels of IRF4 are causally related to CLL development was unclear. In our studies here, we demonstrated that IRF4 deficient mice expressing immunoglobulin heavy chain Vh11 (IRF4-/-Vh11) developed spontaneous CLL with complete penetrance. Additionally, we also show that low levels of IRF4 dramatically accelerates CLL development in the New Zealand Black (NZB) mouse model of CLL. Together, these studies establish a causal role for IRF4 in the development of CLL. Furthermore, we used the IRF4-/-Vh11 as a novel mouse model to CLL to define the molecular mechanism through which IRF4 suppresses CLL development. Our studies identified hyperactivation of Notch signaling pathway as a common feature of IRF4-/-Vh11 CLL cells. Intriguingly, deregulation of Notch signaling pathway has been identified as one of the most recurrent molecular anomalies in the pathogenesis of CLL. Yet, the role of Notch signaling as well as its regulation during CLL development remained unclear. Our studies further reveal that Notch signaling promotes survival and expansion of CLL cells and their precursors and is indispensable for CLL development in the IRF4-/-Vh11 mice. Moreover, we identify E3 ubiquitin ligase Nedd4, which targets Notch for degradation, as a direct target of IRF4 in CLL cells and their precursors. Collectively, our studies here establish a causal role for low levels of IRF4 in the development of CLL. These studies provide the first in vivo evidence for an essential role of Notch signaling in the development of CLL and establish IRF4 as a critical regulator of Notch signaling during CLL development.

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Permission letter JBC

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Permission letter Blood

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