Targeting Polyamine Metabolism in Relapsed Acute Myeloid Leukemia Stem Cells

About This Grant

Project Summary The overall goal of this project is to target and mechanistically interrogate polyamine metabolism in leukemia stem cells (LSCs) with the long-term objective of developing LSC directed therapy to improve the outcomes of patients with acute myeloid leukemia (AML). AML is a devasting disease with a 30% five-year survival rate, in part due to high relapse rates. While most AML patients achieve a clinical response, therapy resistant AML cells often persist post treatment. A subset of therapy resistant cells called leukemia stem cells (LSCs) exist in residual disease and are responsible for driving disease relapse in most AML patients; making it is critically important to develop new therapies to target the LSC population to improve AML patient outcomes. LSCs have unique and targetable metabolic requirements. Using mass spectrometry-based metabolomics analysis, we have shown that the metabolite levels within LSCs isolated from primary AML patients are distinct from their normal counterpart, hematopoietic stem and progenitor cells (HSPCs). Polyamine levels were significantly increased in LSCs compared HSPCs. Pharmacologic depletion of polyamine levels showed that LSCs are reliant on polyamine metabolism for their survival. Polyamines are cationic compounds containing at least two amino groups, that have pleiotropic effects on cell function and importantly have not been examined in LSC biology. Mechanistic interrogation of polyamine biology in LSCs revealed that polyamines are used to regulate protein synthesis. Polyamines regulate mRNA translation by serving as a precursor for the post-translational modification, hypusination, which is essential for the activity of the eukaryotic initiation factor 5A (eIF5A). eIF5A is a translation elongation factor that is important in the synthesis of a subset of proteins that contain amino acid sequences that are less efficient at forming peptide bonds such as proline rich regions. Thus, polyamines may mediate LSC function through the regulation of protein synthesis of select mRNAs that are essential for LSC survival. Based on our preliminary data, we hypothesize that polyamines are required for LSC function through their role in regulating eIF5A-dependent protein synthesis. We will examine this hypothesis by determining the molecular and biological consequences of polyamine depletion in LSCs. (Aim 1). Further, mechanistically dissect the role of polyamines in regulating eIF5A dependent protein synthesis in LSC function (Aim 2). Through these highly translational studies, we expect to determine the importance of polyamine supported eIF5A hypusination on LSC function and evaluate the therapeutic potential of targeting polyamine metabolism in AML. Our studies will reveal novel LSC biology, the mechanisms by which polyamine depletion/reduced eIF5A hypusination decrease LSC function and define potential pathways the mediate resistance to polyamine depletion in LSCs. We anticipate the proposed experiments will serve as the foundation for a future clinical trial targeting polyamine metabolism in AML.