Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis

被引:54
作者
Koh, KR
Janz, M
Mapara, MY
Lemke, B
Stirling, D
Dörken, B
Zenke, M
Lentzsch, S
机构
[1] Osaka City Univ, Dept Clin Hematol & Clin Diagnost, Grad Sch Med, Osaka 558, Japan
[2] Humboldt Univ, Robert Rossle Klin, Med Ctr Charite, Dept Hematol Oncol & Tumorimmunol, Berlin, Germany
[3] Max Delbruck Ctr Mol Med, Berlin, Germany
[4] Univ Pittsburgh, Inst Canc, Div Hematol & Oncol, Pittsburgh, PA 15260 USA
[5] Univ Aachen, Sch Med, Dept Cell Biol, Inst Biomed Engn, D-5100 Aachen, Germany
[6] Celgene, Warren, NJ USA
关键词
D O I
10.1182/blood-2004-03-0828
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-alpha (C/EBP alpha), C/EBP delta, and C/EBP epsilon 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) 2005 by The American Society of Hematology.
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收藏
页码:3833 / 3840
页数:8
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