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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.
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Submitted March 8, 2004
Accepted July 14, 2004
Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis
Ki-Ryang Koh, Martin Janz, Markus Y Mapara, Britt Lemke, David Stirling, Bernd Dorken, Martin Zenke, and Suzanne Lentzsch*
Department of Clinical Hematology and Clinical Diagnostics, Graduate School of Medicine, Osaka City University, Osaka, Japan
Department of Hematology, Oncology and Tumorimmunology, University Medical Center Charite, Robert-Rossle-Klinik, Humboldt University of Berlin, Berlin, Germany; Max-Delbruck-Center for Molecular Medicine, Berlin, Germany
Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Cell Biology, Institute for Biomedical Technology, Universitatsklinikum Aachen, Aachen, Germany
Celgene Corporation, Warren, NJ, USA
* Corresponding author; email: lentzsch{at}rrk.charite-buch.de.
IMiD CC-4047, a new analog of thalidomide, directly inhibits growth of B cell malignancies in vivo and in vitro, and exhibits stronger anti-angiogenic 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, EKLF and Gfi-1b, were down regulated in CC-4047 treated CD34+ cells while myeloid transcription factors such as C/EBP , C/EBP , and C/EBP were induced. Analysis of cytokine secretion indicated that CC-4047 induced secretion of cytokines, which 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.
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