Protein Phosphatase 2A Catalytic Subunit α (PP2Acα) Maintains Survival of Committed Erythroid Cells in Fetal Liver Erythropoiesis through the STAT5 Pathway

Suppression of programmed cell death is critical for the final maturation of red blood cells and depends largely on the anti-apoptotic effects of EpoR-STAT5-Bcl-x(L) signaling. As the major eukaryotic serine/thureonine phosphatase, protein phosphatase 2A (PP2A) regulates multiple cellular processes, including apoptosis. However, whether PP2A plays a role in preventing erythroid cells from undergoing apoptosis remains to be elucidated. We conditionally inactivated the catalytic subunit alpha of PP2A (PP2Ac alpha), which is the predominant form of PP2Ac, during early embryonic hematopoiesis. Loss of PP2Ac alpha in hematopoietic cells perturbed definitive erythropoiesis characterized by fetal liver atrophy, reduced Ter119(+) cell number, abnormal expression patterns of molecular markers, less colony formation, and a reduction in definitive globin expression. Levels of erythropoiesis-promoting cytokines and initial seeding with hematopoietic progenitors remained unchanged in PP2Ac alpha(TKO) fetal livers. We noted impaired expansion of the fetal erythroid compartment, which was associated with increased apoptosis of committed erythroid cells. Mechanistically, PP2Ac alpha depletion markedly reduced Tyr(694) phosphorylation of STAT5 and expression of Bcl-x(L). Unexpectedly, PP2Ac alpha-defident embryos did not manifest any early embryonic vascular defects. Collectively, these data provide direct loss-of-function evidence demonstrating the importance of PP2Aca for the survival of committed erythroid cells during fetal liver erythropoiesis. (AmJ Pathol 2011, 178:2333-2343; DOI: 10.1016/j.ajpath.2011.01.041)