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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3833-3840
Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis
Abstract
Ki-Ryang Koh, Martin Janz, Markus Y. Mapara, Britt Lemke, David Stirling, Bernd Dorken, Martin Zenke, and Suzanne Lentzsch
From 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 Charite Robert-Rossle-Klinik, Humboldt University of Berlin, Germany; Max-Delbruck-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-![](\"http://www.bloodjournal.org/math/alpha.gif\"border=0)
(C/EBP), C/EBP![](\"http://www.bloodjournal.org/math/delta.gif\")
, and C/EBP![](\"http://www.bloodjournal.org/math/epsi.gif\")
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.
(C/EBP), 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.
논문정보
- Research article
- 2005년 05월 (BRIC 등록일 )
- 국외 연구진
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