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Blood, 15 June 2002, Vol. 99, No. 12, pp. 4406-4412
HEMATOPOIESIS
Induction of granulocytic differentiation by 2 pathways
Pu Zhang,
Erik Nelson,
Hanna S. Radomska,
Junko Iwasaki-Arai,
Koichi Akashi,
Alan D. Friedman, and
Daniel G. Tenen
From the Harvard Institutes of Medicine, Harvard
Medical School; and Department of Cancer Immunology and AIDS,
Dana-Farber Cancer Institute; both of Boston, MA; and Johns Hopkins
University, Baltimore, MD.
The CCAAT enhancer binding protein  (C/EBP) transcription
factor plays a critical role in granulocytopoiesis. Mice with a
disruption of the C/EBP gene demonstrate an early block in granulocytic differentiation, and disruption of C/EBP 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-deficient animals. These lines resembled morphologically the immature myeloid blasts observed in
C/EBP / 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 gene into the line revealed that conditional
expression of C/EBP induced the C/EBP family members C/EBP and
C/EBP and subsequent granulocyte differentiation. Similar results
were obtained when C/EBP/ 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.
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