Date on Master's Thesis/Doctoral Dissertation

12-2016

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Beverly, Levi

Committee Co-Chair (if applicable)

Siskind, Leah

Committee Member

Siskind, Leah

Committee Member

Clark, Geoffrey

Committee Member

Yaddanapudi, Kavitha

Committee Member

Basu, Soumit

Author's Keywords

Leukemia; Cancer; Epigenetics; Mouse models

Abstract

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.

Download

Share

COinS