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a Department of Hematology and Oncology, University Hospital, Frankfurt, Germany;
b Department of Hematology, Oncology and Transfusion Medicine, University Hospital Benjamin Franklin, Berlin, Germany;
c Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, California, USA
Key Words. Gene expression • Hematopoietic development • Hematopoietic stem cell • Microarray • Transcription
Correspondence: Wolf-K. Hofmann, M.D., Department of Hematology, Oncology and Transfusion Medicine, University Hospital Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. Telephone: 49-30-8445-3421; Fax: 49-30-8445-4468; e-mail: W.K.Hofmann{at}charite.de
To better understand the transcriptional program that a ccompanies orderly lineage-specific hematopoietic differentiation, we performed serial oligonucleotide microarray analysis of human normal CD34+ bone marrow cells during lineage-specific differentiation. CD34+ bone marrow cells isolated from healthy individuals were selectively stimulated in vitro with the cytokines erythropoietin (EPO), thrombopoietin (TPO), granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF). Cells from each of the lineages were harvested after 4, 7, and 11 days of culture for expression profiling. Gene expression was analyzed by oligonucleotide microarrays (HG-U133A; Affymetrix, Santa Clara, CA). Experiments were done in triplicates. We identified 258 genes that are consistently upregulated or downregulated during the course of lineage-specific differentiation within each specific lineage (horizontal change). In addition, we identified 52 genes that contributed to a specific expression profile, yielding a genetic signature specific for successive stages of differentiation within each of the three lineages. Analysis of horizontal changes selected 21 continuously upregulated genes for EPO-induced differentiation (including GTPase activator proteins RAP1GA1 and ARHGAP8, which regulate small Rho GTPases), 21 for G-CSF–induced/GM-CSF–induced differentiation, and 91 for TPO-induced differentiation (including DLK1, of which the role in normal hematopoiesis is not defined). During the lineage-specific differentiation, 58 (erythropoiesis), 30 (granulopoiesis), and 37 (thrombopoiesis) genes were significantly downregulated, respectively. The expression of selected genes was confirmed by real-time polymerase chain reaction. Our data encompass the first extensive transcriptional profile of human hematopoiesis during in vitro lineage-specific differentiation.
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