Evidence that stem cell factor is involved in the rebound thrombocytosis that follows 5-fluorouracil treatment.
The mechanisms responsible for 5-fluorouracil (5FU)-induced rebound thrombocytosis are not completely understood. SI/SI(d) mice, which do not undergo rebound thrombocytosis in response to 5FU, provide a genetic approach to the study of this phenomenon. Recent reports by several groups that the SI locus encodes a protein known variably as stem cell factor (SCF), mast cell growth factor, or kit ligand, suggests the possibility that the lack of wild-type SCF in SI/SI(d) mice is responsible for their defective response to 5FU-induced thrombocytopenia. It is shown in this report that SCF-treated SI/SI(d) mice are as capable as their wild-type littermates in undergoing rebound thrombocytosis. W/Wv mice, mutated at the locus encoding the SCF receptor, also do not undergo rebound thrombocytosis, but are not responsive to SCF treatment. In normal mice, it is shown by RNA solution hybridization that SCF mRNA expression is increased during the 5FU-induced platelet nadir period. It is also shown by autoradiography that maturing megakaryocytes express SCF receptors, and that in vivo administration of SCF significantly raises the numbers of megakaryocytes, as well as circulating platelet counts. Taken together, these data indicate that SCF may be an important regulator of platelet production under both normal and physiologically disturbed situations.
Hunt
P
P
Amgen, Laboratory of Stem Cell Biology, Amgen Center, Thousand Oaks, CA 91320.
Zsebo
K M
KM
Hokom
M M
MM
Hornkohl
A
A
Birkett
N C
NC
del Castillo
J C
JC
Martin
F
F
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression; D016298:Hematopoietic Cell Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010976:Platelet Count / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D019089:Stem Cell Factor; D013922:Thrombocytosis / Q000139:chemically induced*
D016298:Hematopoietic Cell Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D005472:Fluorouracil