PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in Acute Myeloid Leukemia.

Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. Herein, we identified that the silencing of Protein Phosphatase 2A (PP2A) directly contributes to differentiation block in acute myeloid leukemia (AML). Gene expression and mass cytometric profiling reveal that PP2A activation modulates cell cycle and transcriptional regulators that program terminal myeloid differentiation. Using a novel pharmacological agent OSU-2S in parallel with genetic approaches, we discovered that PP2A enforces c-Myc and p21 dependent terminal differentiation, proliferation arrest and apoptosis in AML. Finally, we demonstrate that PP2A activation decreases leukemia initiating stem cells, increases leukemic blast maturation, and improves overall survival in murine Tet2-/-Flt3ITD/WT and human AML models in-vivo. Our findings identify the PP2A/c-Myc/p21 axis as a critical regulator of the differentiation/proliferation switch in AML that can be therapeutically targeted in malignancies with dysregulated maturation fate.