Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis.
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/EBPalpha), C/EBPdelta, and C/EBPepsilon 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.
Department of Clinical Hematology and Clinical Diagnostics, Graduate School of Medicine, Osaka City University, Japan.
Ki-Ryang
KR
Koh
Martin
M
Janz
Markus Y
MY
Mapara
Britt
B
Lemke
David
D
Stirling
Bernd
B
Dörken
Martin
M
Zenke
Suzanne
S
Lentzsch
D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D038042:Myelopoiesis / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
D016207:Cytokines; D014157:Transcription Factors; D013792:Thalidomide; C467566:pomalidomide