GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression

The transcription factor GATA-1 is essential for normal erythropoiesis, By examining in vitro-differentiated embryonic stem cells, we showed previously that in the absence of GATA-1, committed erythroid precursors fail to complete maturation and instead undergo apoptosis. The mechanisms by which GATA-1 controls cell survival are unknown. Here we report that in erythroid cells, GATA-1 strongly induces the expression of the anti-apoptotic protein bcl-x(L), but not the related proteins bcl-2 and mcl-1. Consistent with a role for bcl-x(L) in mediating GATA-1-induced erythroid cell survival, in vitro-differentiated bcl-x(L)(-/-) embryonic stem cells fail to generate viable mature definitive erythroid cells, a phenotype resembling that of GATA-1 gene disruption, In addition, we show that erythropoietin, which is also required for erythroid cell survival, cooperates with GATA-1 to stimulate bcl-x(L) gene expression and to maintain erythroid cell viability during terminal maturation. Together, our data show that bcl-x(L) is essential for normal erythroid development and suggest a regulatory hierarchy in which bcl-x(L) is a critical downstream effector of GATA-1 and erythropoietin-mediated signals. (C) 1999 by The American Society of Hematology.