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

Official URL:https://doi.org/10.1182/blood-2004-03-0828
PubMed:View item in PubMed
Creators Name:Koh, K.R. and Janz, M. and Mapara, M.Y. and Lemke, B. and Stirling, D. and Doerken, B. and Zenke, M. and Lentzsch, S.
Journal Title:Blood
Journal Abbreviation:Blood
Page Range:3833-3840
Date:1 January 2005
Keywords:Cell Differentiation, Cell Lineage, Cultured Cells, Cytokines, Erythroid Cells, Erythropoiesis, Gene Expression Regulation, Myeloid Cells, Myelopoiesis, Stem Cells, Thalidomide, Time Factors, Transcription Factors
Abstract: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-α (C/EBPα), C/EBPδ, and C/EBPϵ 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.
Publisher:American Society of Hematology (U.S.A.)
Item Type:Article

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