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dc.contributor.advisorSwanson, Patricken_US
dc.contributor.authorNganga, Vincent K.en_US
dc.date.accessioned2013-08-02T13:32:19Z
dc.date.available2015-08-01T13:40:09Z
dc.date.issued2013-06-25en_US
dc.identifier.urihttp://hdl.handle.net/10504/45039
dc.description.abstractChronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and mainly affects the elderly. CLL is a heterogeneous disease that is characterized by progressive accumulation of small lymphocytes that express CD19, CD5, and CD23 in the blood and lymphoid organs. The origins of CLL remain unclear but emerging evidence suggests that CLL likely evolves from a more benign biologically similar condition known as monoclonal B cell lymphocytosis. However, what initiates this condition or how it evolves to CLL is unknown.|Recently developed transgenic mice that express catalytically inactive RAG1 in the periphery (dnRAG1 mice) develop an early-onset indolent CD5+ B cell lymphocytosis, caused in part by a defect in secondary V(D)J rearrangements initiated to alter autoreactive B cell receptor specificity. Hypothesizing that the CD5+ B cells accumulating in these animals represent a CLL precursor, dnRAG1 mice were crossed with CLL-prone Eμ-TCL1 mice, which carry the T cell leukemia/lymphoma 1 (TCL1) transgene, to determine whether dnRAG1 expression in Eμ-TCL1 mice accelerates the onset of CLL-like disease. These experiments showed that CD5+ B cell expansion and CLL progression occurred more rapidly and uniformly in double-transgenic mice (DTG mice) compared to Eμ-TCL1 mice, but with similar phenotypic and leukemogenic features. Interestingly, splenic CD3+TCRβ+CD4-CD8- (double-negative) and CD4+CD25+ regulatory T cells increased in frequency as a function of age in DTG mice, suggesting they may be linked to the expanding CD5+ B cells.|Comparative analysis of gene expression profiles in normal and transgenic CD5+ B cells indicate that CLL may develop by distinct but convergent pathways that may be nurtured by loss of tolerance. These studies also reveal a possible role for prolactin signaling in the regulation of receptor editing.|The work in this dissertation suggests that the B cell antigen receptor plays a significant role in CLL pathogenesis in that failure to remodel the receptor in response to autoreactivity may promote the benign accumulation of CD5+ B cells, which may then be subjected to secondary genetic lesions that promote CLL progression.en_US
dc.language.isoen_USen_US
dc.publisherCreighton Universityen_US
dc.rightsCopyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.en_US
dc.subject.meshHomeodomain Proteins--geneticsen_US
dc.subject.meshHomeodomain Proteins--metabolismen_US
dc.subject.meshLeukemia, Lymphocytic, Chronic, B-Cell--geneticsen_US
dc.subject.meshProto-Oncogene Proteins--geneticsen_US
dc.titleAccelerated progression of chronic lymphocytic leukemia in Eµ-TCL1 transgenic mice expressing catalytically-inactive recombination-activating gene 1en_US
dc.typeDissertation
dc.rights.holderVincent K. Ngangaen_US
dc.publisher.locationOmaha, Nebraskaen_US
dc.description.noteProQuest Traditional Publishing Optionen_US
dc.description.pagesxviii, 197 pagesen_US
dc.contributor.cuauthorNganga, Vincent K.en_US
dc.embargo.terms2015-08-01
dc.degree.levelPhD (Doctor of Philosophy)en_US
dc.degree.disciplineMedical Microbiology and Immunology (graduate program)en_US
dc.degree.namePh.D. in Medical Microbiology and Immunologyen_US
dc.degree.grantorGraduate Schoolen_US
dc.degree.committeeBartz, Jasonen_US
dc.degree.committeeBelshan, Michaelen_US
dc.degree.committeeDrescher, kristenen_US
dc.degree.committeeNaushad, Hinaen_US


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