GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-x(L) expression

The transcription factor GATA-1 is essential for normal erythropoiesis, By examining in vitro-differentiated embryonic stem cells, we showed previousl y that in the absence of GATA-1, committed erythroid precursors fail to com plete maturation and instead undergo apoptosis. The mechanisms by which GAT A-1 controls cell survival are unknown. Here we report that in erythroid ce lls, GATA-1 strongly induces the expression of the anti-apoptotic protein b cl-x(L), but not the related proteins bcl-2 and mcl-1. Consistent with a ro le for bcl-x(L) in mediating GATA-1-induced erythroid cell survival, in vit ro-differentiated bcl-x(L)(-/-) embryonic stem cells fail to generate viabl e mature definitive erythroid cells, a phenotype resembling that of GATA-1 gene disruption, In addition, we show that erythropoietin, which is also re quired for erythroid cell survival, cooperates with GATA-1 to stimulate bcl -x(L) gene expression and to maintain erythroid cell viability during termi nal maturation. Together, our data show that bcl-x(L) is essential for norm al 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.