Enhancement of intracellular signaling associated with hematopoietic progenitor cell survival in response to SDF-1/CXCL12 in synergy with other cytokines

Stromal cell-derived factor 1 (SDF-1/ CXCL12) is a multifunctional cytokine. We previously reported that myelopoiesis was enhanced in SDF-1alpha. transgenic mice, probably due in part to SDF-1a enhancement of myeloid progenitor cell (MPC) survival. To understand signaling pathways involved in this activity, we studied the effects on factor-dependent cell line MO7e cells incubated with SDF-1alpha alone or in combination with other cytokines. SDF-1alpha induced transient activation of extracellular stress-regulated kinase (ERK1/2), ribosomal S6 kinase (p9ORSK) and Akt, molecules implicated in cell survival. Moreover, ERK1/2, p9ORSK, and Akt were synergistically activated by SDF-1alpha in combination with granulocyte-macrophage colony-stimulating factor (GMCSF), Steel factor (SLF), or thrombopoietin (TPO). Similar effects were seen after pretreatment of MO7e cells with SDF-1alpha followed by stimulation with the other cytokines, suggesting a priming effect of SDF-1alpha. Nuclear factor-kappaB (NF-kappaB) did not appear to be involved in SDF-1alpha actions, alone or in combination with other cytokines. These intracellular effects were consistent with enhanced myeloid progenitor cell survival by SDF-1alpha. after delayed addition of growth factors. SDF-1alpha, alone supported survival of highly purified human cord blood CD34(+++) cells, less purified human cord blood,and MO7e cells; this effect was synergistically enhanced when SDF-1alpha a was combined with low amounts of other survival-promoting cytokines (GM-CSF, SLF, TPO, and FL). SDF-1 may contribute to maintenance of MPCs in bone marrow by enhancing cell survival alone and in combination with other cytokines. (Blood. 2002;99:4307-4317) (C) 2002 by The American Society of Hematology.