Unraveling distinct intracellular signals that promote survival and proliferation: Study of erythropoietin, stem cell factor, and constitutive signaling in leukemic cells

This review summarizes selected recent studies of the intracellular signals that allow erythroid cells to survive and proliferate under the control of erythropoietin (EPO) and alteration in signals that contribute to EPO-inde pendent survival and proliferation. The hypothesis explored is that the pro liferation and survival signals are distinct and can be separately studied with the proper cell lines and growth factor stimulation. The anti- and pro -apoptotic proteins Bcl-XL and BAD are highly implicated in EPO-dependent s urvival of erythroid cells. Stat5 activity appears to be upstream of Bcl-XL expression such that pathologic, constitutive activation of Stat5 may be a common event in leukemic cells that become resistant to apoptosis by const itutive expression of Bcl-XL. Other signals apparently also control the exp ression of Bcl-XL, such as the expression of JunB which seem to be required to suppress Bcl-XL expression when EPO is withdrawn. Apoptosis may also be triggered by inactivation of Bcl-XL by BAD. Dephosphorylation of BAD as a result of withdrawal of survival factors converts prosurvival BAD to proapo ptotic BAD. Phosphorylation of BAD at the serine 112 residue seems critical to promoting survival. Constitutive activation of a kinase that phosphoryl ates BAD serine 112 may, therefore, contribute to resistance to apoptosis i n leukemic cells. We describe the resistance of erythroleukemic cells to ap optosis induced by EPO withdrawal apparently caused by constitutive BAD pho sphorylation. The resistance to apoptosis in these cells is reversed by tre atment with the PI3-kinase inhibitor, LY294002, suggesting that resistance to apoptosis in these cells likely results from constitutive PI3-kinase tha t is an upstream activator of an S-112 BAD kinase. The MAP kinase cascade i s apparently active in EPO-dependent and stem cell factor (SCF)-dependent p roliferation but not survival. In addition, autocrine tumor necrosis factor -alpha (TNF-alpha) may also be a proliferation factor not affecting surviva l. PI3-kinase seems to be required for full EPO-dependent proliferation but is not required for EPO-dependent survival (but it can promote survival wh en activated).