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Walker, Janek - Dissertation.pdf (12.64 MB)

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Utilizing Laboratory and Mouse Models to Explore High-Risk Genetic Determinants of Chronic Lymphocytic Leukemia

Walker, Janek S
http://orcid.org/0000-0002-2049-1527
http://rave.ohiolink.edu/etdc/view?acc_num=osu1657110861089719

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the United States, historically characterized by significant genetic and clinical heterogeneity. Most patients are asymptomatic at diagnosis, where slow progression of the indolent CLL tumor burden is manageable to the point where patients can comfortably live with this disease for the full extent of their natural lifespan. Many patients, however, experience rapid tumor progression that requires intensive clinical intervention. Further, up to 10% of patients experience a morphologic CLL evolution to a rapidly progressing large B cell lymphoma, termed Richter’s Transformation, with abysmal survival outcomes frequently less than 12 months from the time of diagnosis. Advances in the understanding of CLL tumor biology have led to development of several targeted therapeutic strategies that have dramatically improved outcomes in patients with more rapid progression, nearly removing the need for systems-based cytotoxic and chemotherapeutic regimens. Despite the tremendous success with these targeted therapies, not all patients respond favorably, and new observations of therapeutic resistance and disease relapse are increasing with long term treatment using these compounds. Thus, CLL remains an incurable disease, requiring further investigation to identify treatment strategies in high-risk patient populations. Advances in genome editing techniques and tools to generate laboratory and mouse models have streamlined our understanding of genetic and epigenetic aberrations in CLL by allowing for their evaluation in the context of mammalian systems resembling the CLL disease environment. However, there remains an incomplete understanding of the physiologic impact for many the putative driving genes and cytogenetic aberrations regarding their contribution to CLL biology, and most of the CLL-specific models do not entirely recapitulate what is observed in CLL patients. Compounding this situation, no unifying genetic event has been identified in all CLL cases, making the presently available CLL tumor models inadequate for studying systems applicable to a majority of CLL patients. Overall, highlighting a need for further development of CLL models to provide a more robust characterization of the genetic complexity in CLL patients. To address this need, in these studies we have generated a suite of novel laboratory and mouse models with the intent of evaluating previously unexplored genetic aberrations with strong associations to cases of advanced CLL. Here, we explore the leukemogenic potential of recurrent E571 XPO1 mutations and discuss their role in transformation from healthy to neoplastic B cells, we use the observation of a novel chromosome translocation, t(X;14)(q28;q32), to evaluate a role for the MTCP1 gene in the development and progression of CLL, and lastly we identify aberrant PRMT5 expression as a mechanism promoting the rapid evolution from CLL to Richter’s Transformation. Using rationale from genetic aberrations in CLL patients at The Ohio State University to establish these models, we provide evidence to support aberrations in XPO1, MTCP1, and PRMT5 as major contributing factors in advanced CLL. Importantly, these new models are ideally suited for further characterization of CLL disease biology and for pre-clinical evaluation of novel therapeutic strategies for high risk CLL patients.
Rosa Lapalombella (Advisor)
John Byrd (Committee Member)
Jennifer Woyach (Committee Member)
Eugene Oltz (Committee Member)
320 p.
Biochemistry; Bioinformatics; Cellular Biology; Health Sciences; Immunology; Molecular Biology; Oncology; Pharmaceuticals
CLL, XPO1, MTCP1, PRMT5, Selinexor

Recommended Citations

Citations

  • Walker, J. S. (2022). Utilizing Laboratory and Mouse Models to Explore High-Risk Genetic Determinants of Chronic Lymphocytic Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1657110861089719

    APA Style (7th edition)

  • Walker, Janek. Utilizing Laboratory and Mouse Models to Explore High-Risk Genetic Determinants of Chronic Lymphocytic Leukemia. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1657110861089719.

    MLA Style (8th edition)

  • Walker, Janek. "Utilizing Laboratory and Mouse Models to Explore High-Risk Genetic Determinants of Chronic Lymphocytic Leukemia." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1657110861089719

    Chicago Manual of Style (17th edition)

osu1657110861089719
168
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This open access ETD is published by The Ohio State University and OhioLINK.