PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in Acute Myeloid Leukemia.
Swagata GoswamiRajeswaran ManiJessica NunesChi-Ling ChiangKevan ZapolnikEileen Y HuFrank W FrissoraXiaokui M MoLogan A WalkerPearlly S YanRalf BundschuhLarry BeaverRaymond David DevineYo-Ting TsaiAnn Marie VenturaZhiliang XieMin ChenRosa LapalombellaAlison R WalkerAlice S MimsKarilyn T M LarkinNicole Renee GrieselhuberChad BennettMitch A PhelpsErin K HertleinGregory K BehbehaniSumithira VasuJohn C ByrdNatarajan MuthusamyPublished in: Blood (2021)
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.
Keyphrases
- acute myeloid leukemia
- cell cycle
- gene expression
- stem cells
- allogeneic hematopoietic stem cell transplantation
- transcription factor
- signaling pathway
- cell fate
- cell proliferation
- mesenchymal stem cells
- bone marrow
- endothelial cells
- endoplasmic reticulum stress
- small molecule
- liver failure
- cell death
- protein protein
- drug delivery
- tyrosine kinase
- binding protein
- respiratory failure
- free survival
- cancer therapy
- cell cycle arrest
- acute respiratory distress syndrome