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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3833-3840. Prepublished online as a Blood First Edition Paper on August 3, 2004; DOI 10.1182/blood-2004-03-0828.
HEMATOPOIESIS Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesisFrom the Department of Clinical Hematology and Clinical Diagnostics, Graduate School of Medicine, Osaka City University, Japan; Department of Hematology, Oncology and Tumorimmunology, University Medical Center Charité, Robert-Rössle-Klinik, Humboldt University of Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, PA; Department of Cell Biology, Institute for Biomedical Engineering, Aachen University Medical School, Reihisch-Westfaelische Technische Hochschule, Aachen, Germany; and Celgene, Warren, NJ.
Immunomodulatory derivative (IMiD) CC-4047, a new analog of thalidomide, directly inhibits growth of B-cell malignancies in vivo and in vitro and exhibits stronger antiangiogenic activity than thalidomide. However, there is little information on whether CC-4047 affects normal hematopoiesis. Here we investigated the effect of CC-4047 on lineage commitment and differentiation of hematopoietic stem cells. We found that CC-4047 effectively inhibits erythroid cell colony formation from CD34+ cells and increases the frequency of myeloid colonies. We also demonstrate that development of both erythropoietin-independent and erythropoietin-dependent red cell progenitors was strongly inhibited by CC-4047, while terminal red cell differentiation was unaffected. DNA microarray analysis revealed that red cell transcription factors, including GATA-1, GATA-2, erythroid Kruppel-like factor (EKLF), and growth factor independence-1B (Gfi-1b), were down-regulated in CC-4047–treated CD34+ cells, while myeloid transcription factors such as CCAAT/enhancer binding protein-
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
(C/EBP
, and C/EBP
were induced. Analysis of cytokine secretion indicated that CC-4047 induced secretion of cytokines that enhance myelopoiesis and inhibit erythropoiesis. In conclusion, these data indicate that CC-4047 might directly influence lineage commitment of hematopoietic cells by increasing the propensity of stem and/or progenitor cells to undergo myeloid cell development and concomitantly inhibiting red cell development. Therefore, CC-4047 provides a valuable tool to study the mechanisms underlying lineage commitment. 
