Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, MS
Committee Co-Chair (if applicable)
Leukemia; Cancer; Epigenetics; Mouse models
Acute myeloid leukemia (AML) is a highly heterogeneous clonal disorder characterized by an accumulation of malignant immature myeloid progenitors in the bone marrow (BM) that hinder normal hematopoiesis. Patient AML exhibits a dramatic heterogeneity in terms of cytogenetics, disease morphology, and associated prognoses and/or chemotherapeutic sensitivity. Thus it becomes clearly evident that the investigation of novel therapeutics for AML will require model systems that are capable of recapitulating this stark heterogeneity in a patient specific manner. Furthermore, it is now understood that the surrounding bone marrow (BM) microenvironment and supporting cells play a critical role in leukemic progression as well as providing a chemotherapy protected sanctuary for residual disease. Therefore, the focus of this study was the establishment and development of a more clinically relevant mouse xenograft model of patient derived AML that not only recapitulates patient disease but also simulates the clinical standard of care induction therapy. The crux of our model system was the NRGS mouse, which were not only capable of reliable high rates of engraftment of established cell lines and patient derived AML cells, but also expresses three human myeloid cytokines (IL-3, GM-CSF, SF). Additionally these mice were able to tolerate aggressive induction therapy at doses similar to those administered to patients, and therapy was efficacious in prolonging the survival of mice engrafted with patient AML. Such model systems that can simulate patient specific AML along with the standard of care therapy, will be essential for the successful investigation of novel, translational therapeutics.
Barve, Aditya, "Establishing a clinically relevant mouse model of human AML to test novel transmethylation inhibitors." (2016). Electronic Theses and Dissertations. Paper 2615.