AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. AMPK is a metabolic regulator that promotes catabolism and inhibits anabolism, thereby maintaining metabolic homeostasis upon metabolic stress. Using mouse models and AMPK inhibitors, we demonstrated that AMPK inhibition renders AML sensitive to metabolic stress induced by dietary restriction (Saito et al. Cell Stem Cell. 2015). During this study, we noticed that AMPK deletion reduces acetyl-coA and histone acetylation in AML (Fig. 2), concomitant with decreased expression of critical leukemia-promoting genes such as Myc. Importantly, chromatin immunoprecipitation and sequencing (ChIP-seq) revealed that AMPK deletion reduces the occupancy of acetylated histones, all of which marks active genes and recruits transcriptional regulators. We thus hypothesized that AMPK links metabolism to epigenetics in AML by maintaining histone acetylation.
In aim 1 we will determine whether the occupancy of transcriptional regulators in AML is regulated by AMPK.
In aim 2, we will determine how metabolites and the metabolic enzymes that produces acetyl-coA regulate histone acetylation.
In aim 3, we will determine how AMPK-mediated histone acetylation regulates human AML, by generating patient-derived xenograft models of AML. Taken together, this proposal will establish the link between metabolism and epigenetics, more specifically the links between acetyl-CoA metabolism, AMPK, and histone acetylation. We hypothesize that these interactions are essential to recruit transcriptional regulators to key leukemogenic genes. In the next funding cycle, we anticipate to unveil new insights that will inform us on how metabolic regulators could be targeted to sensitize AML to epigenetic drugs, paving the way to novel combinatorial therapies.
Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a devastating prognosis for elderly patients. We discovered an unexpected link between metabolism and gene expression in AML, and we will interrogate this mechanism in animal models and patient samples to examine whether we could therapeutically target this mechanism to treat AML. Our study may lead to a novel combinatorial therapy that could deeply suppress AML.
