Personalized Metabolic Targeting of Epigenetic AML Mutations Through the Alpha-Ketoglutarate Pathway
Ravindra Majeti
PhD, MDStanford
Project Term: October 1, 2020 - September 30, 2023
AML is characterized by founder mutations in epigenetic regulators that perturb alpha-ketoglutarate flux to block differentiation and rewire metabolism exposing new druggable vulnerabilities. By integrating bioenergetics and 5hmC profiling in primary cells, we have discovered unexpected 2-hydroxyglutarate-independent vulnerabilities for TET2, IDH1, IDH2, WT1, and CEBPA mutations. Here, we propose mutation-directed drug development for AML through targeting of the alpha-ketoglutarate pathway.
Acute myeloid leukemia (AML) is a devastating blood cancer that affects both young and elderly persons and for which treatment outcomes have not improved for more than 30 years even with standard high dose chemotherapy regimens. Leukemia cells have a block in their ability to mature into normal blood cells for reasons that are only partially understood, but derive in part from mutations acquired in these cells. We were among the first to discover stem cells from the bone marrow of AML patients that carried these mutations eventually leading to the outgrowth of leukemia. Intriguingly, many of these mutations alter stem cell maturation into functional blood cells, a process termed differentiation, by interfering with the mechanisms through which different genes are expressed, such as hydroxymethylation DNA modification and histone acetylation marks. Our research has recently discovered a strong link between the metabolism of leukemia cells and common leukemia-causing mutations through modulation of a central metabolic factor termed alpha ketoglutarate. This work has opened up a major new branch of research and opportunities to eradicate leukemia by changing metabolic profiles. We find that some mutations in AML decrease alpha ketoglutarate effects on DNA and histones (TET2 mutations) while other mutations change the ability of alpha ketoglutarate to generate energy in the mitochondria of cells (CEBPA mutations). Moreover, other mutations cause defects in shuttling alpha ketoglutarate to build new fatty acids to make cell membranes (IDH1 mutations). All of these metabolic changes represent new vulnerabilities that can be exploited for novel therapeutic approaches. We have developed innovative methods involving small numbers of leukemia cells from patients that can assess the fate of alpha ketoglutarate-dependent reactions on DNA, histones, lipid production, and energy metabolism. Here, we propose to apply to these methods to characterize a large number of AML patient samples to inform a precision medicine therapy approach. Furthermore, we propose to investigate pharmacologic agents targeting these alpha ketoglutarate-dependent reactions using patient samples in the lab and in animal models. Our overall objective is to develop a personalized medicine approach through metabolic targeting to deliver mutation-directed therapies to AML patients.