Induction of granulocytic differentiation by 2 pathways.
The CCAAT enhancer binding protein alpha (C/EBP alpha) transcription factor plays a critical role in granulocytopoiesis. Mice with a disruption of the C/EBP alpha gene demonstrate an early block in granulocytic differentiation, and disruption of C/EBP alpha function is a common theme in many types of human acute myelogenous leukemia, which is characterized by a block in myeloid development. To characterize further the nature of this block, we derived cell lines from the fetal liver of C/EBP alpha-deficient animals. These lines resembled morphologically the immature myeloid blasts observed in C/EBP alpha(-/-) fetal livers and did not express messenger RNA encoding early myeloid genes such as myeloperoxidase. Similarly, granulocytic markers such as Mac-1 and Gr-1 were not expressed; nor were erythroid and lymphoid surface antigens. Introduction of an inducible C/EBP alpha gene into the line revealed that conditional expression of C/EBP alpha induced the C/EBP family members C/EBP beta and C/EBP epsilon and subsequent granulocyte differentiation. Similar results were obtained when C/EBP alpha(-/-) cells were stimulated with the cytokines interleukin-3 and granulocyte-macrophage colony-stimulating factor, but not with all-trans retinoic acid, supporting a model of at least 2 pathways leading to the differentiation of myeloid progenitors to granulocytes and implicating induction of other C/EBP family members in granulopoiesis.
Zhang
Pu
P
Harvard Institutes of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Nelson
Erik
E
Radomska
Hanna S
HS
Iwasaki-Arai
Junko
J
Akashi
Koichi
K
Friedman
Alan D
AD
Tenen
Daniel G
DG
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000187:drug effects / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D005333:Fetus / Q000166:cytology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology*; D006410:Hematopoiesis / Q000187:drug effects*; D007377:Interleukin-3 / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C489468:Cebpe protein, mouse; D007377:Interleukin-3; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor