The identification and characterization of a novel human differentiation-inhibiting protein that selectively blocks erythroid differentiation.
We have isolated a novel inhibitor of erythropoietic differentiation from the plasma of a patient suffering from idiopathic pure red cell aplasia. This differentiation-inhibiting protein (DIP) specifically blocked the differentiation of human burst-forming unit-erythroid (BFU-E), but not colony-forming unit-erythroid (CFU-E) cells. DIP also blocked the maturation of murine BFU-E cells, but not CFU-E or CFU-granulocyte-macrophage cells, and it inhibited the dimethyl sulfoxide (DMSO)-induced differentiation of Friend murine erythroleukemia cells (FLC) at levels between 10(-10) and 10(-12) mol/L. DIP activity was not detectable in the plasma of normal, healthy subjects. Unlike other known inhibitors of hematopoiesis, DIP appears to directly inhibit erythropoietic differentiation, because it did not affect the proliferation of untreated FLC and it effectively blocked FLC hemoglobinization without affecting the ability of the blocked cells to proliferate. DIP blocked FLC differentiation only when added to the culture medium within 1 hour of inducing the cells with DMSO, suggesting that the protein inhibited an early, but critical, DMSO-induced cellular process. DIP appears to be at least partially responsible for the patient's anemia, and its unique activity suggests a role in the early development of some erythroleukemias.
Durkin
J P
JP
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario.
Biquard
J M
JM
Whitfield
J F
JF
Morardet
N
N
Royer
J
J
Macdonald
P
P
Tremblay
R
R
Legal
J D
JD
Doyonnas
R
R
Blanchet
J P
JP
D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects; D005260:Female; D005622:Friend murine leukemia virus; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D008970:Molecular Weight; D012010:Red-Cell Aplasia, Pure / Q000097:blood*; D014407:Tumor Cells, Cultured
D001798:Blood Proteins; D004121:Dimethyl Sulfoxide