Disruption of NEDD8 protein conjugation as a novel therapy for acute myeloid leukemia

Swords, Ronan
The coordinated balance between the synthesis and degradation of proteins is an important regulator of cancer cell biology. The ubiquitin-proteasome system (UPS) is responsible for the timed destruction of many proteins including key mediators of fundamental signaling cascades and critical regulators of cell cycle progression and transcription. Within the UPS, the E3 ligases are multi-protein complexes whose specificity is established by their individual components as well as post-translational modifications by various factors including the ubiquitin-like molecule, Nedd8. The Nedd8 activating enzyme (NAE) has been identified as an essential regulator of the Nedd8 conjugation pathway. Considering that Nedd8-mediated control of protein homeostasis is vitally important for the survival of myeloblasts in acute myeloid leukemia (AML), we hypothesized that disrupting this process would result in anti-tumor activity.The overall aim of this thesis then, was to explore the activity of a new anti-leukemia agent both in the laboratory and in the clinic, as a means to improve the outcomes for AML patients that are in critical need of more effective therapies.
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland