Metabolic reprogramming in Acute Myeloid Leukemia

Although outcomes for leukemia patients have improved over the last several years, many patients relapse and succumb to the disease. Therefore, in order to address the urgent need for improvements in clinical outcomes, I am dedicating my doctoral training to understanding the unique metabolism of leukemic stem cells (LSCs) for the development of more effective therapies. My research interests are focused on characterizing metabolic perturbations in acute myeloid leukemia (AML), how altered metabolic pathways contribute to the pathogenesis of LSCs, and how they can be therapeutically targeted. During my work as a professional research assistant at CU Anschutz, much of my time was spent on collaborations with the Linda Crnic Institute, where we discovered unique and significant metabolic derangements in individuals with Down syndrome. (Culp-Hill et al. Blood Adv. Dec 2017.) In the latter half of my time as a research assistant, I focused on a collaboration with the Jordan Lab. We interrogated the metabolome of leukemic stem cells (LSCs) from patients with AML to identify unique properties relevant to therapeutic intervention. LSCs isolated from de novo AML patients are uniquely reliant on both oxidative phosphorylation (OXPHOS) and amino acid metabolism for survival. This property can be metabolically targeted with the combination of venetoclax, a BCL-2 inhibitor, and azacitidine, a DNA demethylase. Disrupting the metabolic machinery driving energy metabolism by therapeutic intervention specifically targeting LSCs leads to the deep and durable remissions in AML patients. (Pollyea et al. Nature Medicine Nov 2018, Jones et al. Cancer Cell Nov 2018) However, certain populations of AML patients are resistant to this treatment. These stem cells display an increase in fatty acid metabolism and desaturation (Stevens et al. Nature Cancer Aug 2020), which may drive the TCA cycle even with inhibition of amino acid metabolism. Preliminary research from this project has become the foundation for my thesis work as a graduate student, which has focused on aberrant fatty acid metabolism and desaturation in AML LSCs. This research may offer a novel therapeutic target for relapsed/refractory AML patients who are resistant to other methods of treatment.