PP2A dependent modulation of c-Myc and p21 leads to differentiation and cell cycle control in Acute Myeloid Leukemia

Aberrant kinase and phosphatase activity frequently contribute to Acute Myeloid Leukemia. Here we characterize the Protein Phosphatase 2A (PP2A) as a mediator of differentiation and cell cycle arrest in AML. Using a novel PP2A activator OSU-2S, we show that PP2A activation results in differentiation, growth arrest and cell death in AML, via depletion of c-Myc and upregulation of p21. Gene expression and mass cytometric profiling further show modulation of cell cycle regulators and differentiation factors, and importantly, decreased CD34+/CD38- stem cells in patient derived AML blasts treated with OSU-2S. Finally, we demonstrate in-vivo therapeutic efficacy of OSU-2S as seen by increased differentiation, decreased clonogenicity and improved survival in a Tet2-/-Flt3ITD murine AML model and human AML models. Overall design: AML cultured cells were either treated with either by vehicle or OSU-2S, 3 replicates of each