PKM2 modulation regulates leukemia cell survival.

Acute myeloid leukemia (AML) cells exhibit aberrant metabolism defined by a shift away from oxidative phosphorylation and towards anaerobic glycolysis, favouring cell growth. Glycolytic enzymes are altered for this change to occur, including pyruvate kinase (PK), where the tetrameric and high activity M1 isoform (PKM1) is replaced with the predominantly dimeric and low activity M2 isoform (PKM2). Dimeric PKM2 produces less pyruvate and acts as a protein kinase in the nucleus, demonstrating divergent roles in both cell metabolism and as a transcriptional co-activator. In this study, the role of PKM2 in AML was defined, as PKM2 levels were elevated but PK enzymatic activity was reduced in AML cells compared to normal hematopoietic cells. Genetic and pharmacological studies show that decreasing and increasing PKM2 activity resulted in anti-AML effects both in vitro and in vivo. Indeed, these models show that inhibition and activation of PKM2 disrupt the native oligomeric state of the protein, resulting in reduced nuclear PKM2 accumulation and c-Myc expression, ultimately leading to cell death. Together, these results highlight the importance of PKM2 in AML, uncover the mechanisms by which both inhibition and activation cause AML cell death, and identify a novel modulator of PKM2 activity.