In aplastic anemia progenitor cells have a reduced sensitivity to the effects of growth factors

We have recently shown that in patients with aplastic anemia (AA) recoverin g following immunosuppressive therapy, the persistent reduction in the bone marrow clonogenic potential is unrelated to suppressive effects of the mye loid stroma and intrinsic to the hematopoietic progenitors. We examined the mechanisms of this defect by determining the response of the aplastic CD34 + clonogenic precursors to proliferative signals induced by hematopoietic growth factors and comparing their results with those of a control populati on. Light density bone marrow mononuclear cells were lymphocyte and monocyt e depleted and enhanced for the CD34 + progenitors by immunomagnetic select ion. Selected progenitors were then cultured in the mixed colony assay with incremental concentrations of combinations containing erythropoietin (Epo) , granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and c-kit ligand. Bone marrow from aplastic patients had significant ly fewer light density cells displaying the CD34 antigen (mean 0.65%, SD 0. 35 vs. 1.62%, SD 1.4; p=0.002). Dose response studies on aplastic CD34 + ce lls demonstrated that at low concentrations of Epo, IL-3 and GM-CSF, clonog enic growth was significantly impaired but achieved normal values at concen trations giving plateau growth in control cultures. However, for all colony types, responses to effective concentrations of c-kit ligand corresponded with those of controls. These data suggest abnormalities at the receptor or signal transduction levels.