Role of the KIT protooncogene in normal and malignant human hematopoiesis.
The role of the KIT protooncogene in human hematopoiesis is uncertain. Therefore, we examined KIT mRNA expression in normal human bone marrow mononuclear cells (MNC) and used antisense oligodeoxynucleotides (oligomers) to disrupt KIT function. KIT mRNA was detected with certainty only in growth factor-stimulated MNC. Expression was essentially abrogated by making MNC quiescent or by inhibiting myb gene function. Oligomers blocked KIT mRNA expression in a dose-response and sequence-specific manner, thereby allowing functional examination of the KIT receptor. In experiments with either partially purified or CD34(+)-enriched MNC, neither granulocyte nor megakaryocyte colony formation was inhibited by oligomer exposure. In contrast, KIT antisense oligomers inhibited interleukin 3/erythropoietin-driven erythroid colony formation approximately 70% and "stem cell factor"/erythropoietin-driven colony formation 100%. The presence of erythroid progenitor cell subsets with differential requirements for KIT function is therefore suggested. Growth of hematopoietic colonies from chronic myeloid leukemia and polycythemia vera patients was also inhibited, while acute leukemia colony growth appeared less sensitive to KIT deprivation. These results suggest that KIT plays a predominant role in normal erythropoiesis but may be important in regulating some types of malignant hematopoietic cell growth as well. They also suggest that KIT expression is linked to cell metabolic activity and that its expression may be regulated by or coregulated with MYB.
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia 19104.
M Z
MZ
Ratajczak
S M
SM
Luger
K
K
DeRiel
J
J
Abrahm
B
B
Calabretta
A M
AM
Gewirtz
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D001483:Base Sequence; D004920:Erythropoiesis; D015870:Gene Expression; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000503:physiopathology*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit; D011519:Proto-Oncogenes; D016372:RNA, Antisense; D012333:RNA, Messenger / Q000235:genetics
D015703:Antigens, CD; D018952:Antigens, CD34; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; D019009:Proto-Oncogene Proteins c-kit