2014 Theses Master's

Bridging the Gap Between Our Understanding of AML Pathogenesis and the Development of Targeted Therapies

Tavakkoli, Montreh

Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in the U.S., with an annual incidence of ~15,000 per year. The median age of diagnosis is 67 years, however, AML afflicts individuals of all ages. Within the past 4 decades, only modest improvements have been made in the treatment of AML. However, the advent of DNA sequencing technologies, fluorescence-activated cell sorting, flow cytometry, and immunodeficient murine models have significantly improved our understanding of the molecular and cellular changes that promote the development of AML. The purpose of my thesis is to explain our current understanding of malignant transformation in AML, and to describe how this knowledge has aided the clinical assessment and treatment of this disease. In order to demonstrate this, I will provide an introduction to the epidemiology and clinical manifestations of AML, the molecular mechanisms underlying its pathogenesis, and new methods to risk-stratify and treat the disease. I will then provide a thorough discussion on normal hematopoiesis and the cellular mechanisms of AML pathogenesis (in the context of the cancer stem cell theory), and will conclude with a brief summary on a novel leukemic stem cell-directed therapy that we are currently developing in our laboratory. For the first time in over 40 years, drastic changes are underway in the way we evaluate and treat AML.