Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis
Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis
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DOI：
10.1182/blood-2004-03-0828
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发表时间：
2005-05-15
期刊：
影响因子：
20.3
通讯作者：
Lentzsch, S
中科院分区：
文献类型：
--
作者：
Koh, KR;Janz, M;Lentzsch, S
免疫调节衍生物 (IMiD) CC-4047 是沙利度胺的新型类似物，可在体内和体外直接抑制 B 细胞恶性肿瘤的生长，并表现出比沙利度胺更强的抗血管生成活性。然而，关于 CC-4047 是否影响正常造血功能的信息很少。在这里，我们研究了 CC-4047 对造血干细胞谱系定型和分化的影响。我们发现CC-4047能有效抑制CD34(+)细胞形成红系细胞集落，并增加骨髓细胞集落的频率。我们还证明，CC-4047 强烈抑制促红细胞生成素非依赖性和促红细胞生成素依赖性红细胞祖细胞的发育，而终末红细胞分化不受影响。 DNA微阵列分析显示，红细胞转录因子，包括GATA-1、GATA-2、红细胞Kruppel样因子(EKLF)和生长因子独立-1B(Gfi-1b)，在CC-4047处理的CD34(+)细胞中下调，而骨髓转录因子如CCAAT/增强子结合蛋白-α(C/EBP α)、C/EBP δ和C/EBP epsilon则下调。诱发。细胞因子分泌分析表明，CC-4047 诱导细胞因子分泌，增强骨髓生成并抑制红细胞生成。总之，这些数据表明 CC-4047 可能通过增加干细胞和/或祖细胞进行骨髓细胞发育的倾向并同时抑制红细胞发育来直接影响造血细胞的谱系定型。因此，CC-4047 为研究谱系承诺的机制提供了一个有价值的工具。 (c) 2005 年，美国血液学会。
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.