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) recovering following immunosuppressive therapy, the persistent reduction in the bone marrow clonogenic potential is unrelated to suppressive effects of the myeloid 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 population. Light density bone marrow mononuclear cells were lymphocyte and monocyte depleted and enhanced for the CD34+ progenitors by immunomagnetic selection. 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 significantly 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+ cells demonstrated that at low concentrations of Epo, IL-3 and GM-CSF, clonogenic growth was significantly impaired but achieved normal values at concentrations 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.
Novitzky
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The University of Cape Town Leukaemia Centre and the Department of Haematology, Groote Schuur Hospital, Observatory, Cape, South Africa. novitzky@samiot.uct.ac.za
Jacobs
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P
D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000097:blood* / Q000188:drug therapy; D018952:Antigens, CD34 / Q000032:analysis; D015331:Cohort Studies; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007377:Interleukin-3 / Q000494:pharmacology; D008875:Middle Aged; D015999:Multivariate Analysis; D010865:Pilot Projects; D019089:Stem Cell Factor / Q000494:pharmacology
D018952:Antigens, CD34; D016298:Hematopoietic Cell Growth Factors; D007166:Immunosuppressive Agents; D007377:Interleukin-3; D019089:Stem Cell Factor; D004921:Erythropoietin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor