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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1546.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2206-2214
HEMATOPOIESIS
Induction of C/EBP activity alters gene expression and
differentiation of human CD34+ cells
Jörg Cammenga,
James
C. Mulloy,
Francisco J. Berguido,
Donal MacGrogan,
Agnes Viale, and
Stephen D. Nimer
From the Laboratory of Molecular Aspects of
Hematopoiesis, Sloan-Kettering Institute, Genomics Core Laboratory and
Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer
Center (MSKCC), New York, NY.
The CCAAT/enhancer binding protein alpha (C/EBP ) belongs
to a family of transcription factors that are involved in the
differentiation process of numerous tissues, including the liver and
hematopoietic cells. C/EBP / mice show a block in
hematopoietic differentiation, with an accumulation of myeloblasts and
an absence of mature granulocytes, whereas expression of C/EBP in
leukemia cell lines leads to granulocytic differentiation. Recently,
dominant-negative mutations in the C/EBP gene and
down-regulation of C/EBP by AML1-ETO, an AML associated fusion
protein, have been identified in acute myelogenous leukemia (AML). To
better understand the role of C/EBP in the lineage commitment and
differentiation of hematopoietic progenitors, we transduced primary
human CD34+ cells with a retroviral construct that
expresses the C/EBP cDNA fused in-frame with the estrogen receptor
ligand-binding domain. Induction of C/EBP function in primary human
CD34+ cells, by the addition of  -estradiol, leads to
granulocytic differentiation and inhibits erythrocyte differentiation.
Using Affymetrix (Santa Clara, CA) oligonucleotide arrays we
have identified C/EBP target genes in primary human
hematopoietic cells, including granulocyte-specific genes that are
involved in hematopoietic differentiation and inhibitor of
differentiation 1 (Id1), a transcriptional repressor known to interfere with erythrocyte differentiation. Given
the known differences in murine and human promoter regulatory sequences, this inducible system allows the identification of transcription factor target genes in a physiologic, human hematopoietic progenitor cell background.
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