AMPK Protects Against Energy Stress and Maintains Histone Acetylation in Leukemia-Initiating-Cell

Maintaining metabolic homeostasis is a fundamental requirement for cells to survive. One critical requirement is to accomplish a balance between anabolism and catabolism. AMPK regulates this balance by directly sensing AMP-to-ATP ratio and its activation during cell energy deficit promotes ATP production and inhibits ATP usage.

Several pieces of evidence point AMPK as a tumor suppressor: the upstream protein, LKB1, is a well-established tumor suppressor; AMPK negatively interacts with the tumor promoting mTOR pathway; anti-diabetic drugs such as metformin with tumor preventive potential are shown to activate AMPK. However, emerging evidence accumulates to support an opposite role of AMPK in promoting tumor growth. AMPK is found to protect tumor cells from metabolic crisis through different mechanisms: autophagy induction; maintaining proper ATP levels and redox environment; histone H2B tail phosphorylation. These two contrasting findings suggested multiple facets of AMPK, thus pointing to the urge to understand mechanisms of AMPK in specific contexts.

We examined the role of AMPK by deleting both α1 and α2 subunit in a mouse model of acute myeloid leukemia with t(9;11) translocation. AMPK deficiency depletes the leukemia-initiating-cell population and decreases the leukemogenic potential of these cells. In order to study the metabolic regulatory effects of AMPK, we profiled the metabolites and found AMPK deficiency associates with a decreased level of glycolytic activity and reduction of acetyl-CoA, which is the major donor for histone acetylation.

Therefore, we hypothesized that AMPK can affect histone acetylation through regulating the level of acetyl-CoA, and functionally alter leukemogenic potential. We first profiled histone acetylation using western blot with antibodies targeting global histone acetylation and specific histone residues. Intriguingly, we found in AMPK-deficient cells, global histone H3 and H4 acetylation levels are decreased, as well as acetylation at specific histone residues such as H3K9, H3K27 and H4K8. To build a causal link between decreased acetyl-CoA and histone acetylation, we supplemented leukemia-initiating-cells in culture with acetyl-CoA precursors such as acetate and pyruvate. The supplementation successfully increased intracellular acetyl-CoA levels as well as histone acetylation levels. Functionally restoring the intracellular acetyl-CoA and histone acetylation increased the proliferative potential of AMPK-deficient leukemia-initiating-cells and maintained cell at a more undifferentiated state. These results suggest that AMPK regulates a set of leukemogenic genes by maintaining histone acetylation levels. We hypothesize that AMPK links metabolic status to epigenetic gene regulation to promote leukemogenesis.