Klump Hannes, Schiedlmeier Bernhard, Baum Christopher
Department of Hematology, Hemostaseology, and Oncology, Laboratory of Experimental Cell Therapy (LECT), Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Ann N Y Acad Sci. 2005 Jun;1044:6-15. doi: 10.1196/annals.1349.002.
The homeodomain transcription factor HOXB4 is one of the most attractive tools to expand hematopoietic stem cells in vitro and in vivo and to promote the formation of hematopoietic cells from in vitro differentiated embryonic stem cells. However, the expression levels compatible with the favorable effect of enhanced self-renewal without perturbing differentiation, in vivo, remain to be determined. In this paper, we discuss the necessity to define the "therapeutic width" of HOXB4 expression, based on observations from our lab and others that demonstrate that ectopic HOXB4 expression leads to a concentration-dependent perturbation of lineage differentiation of mouse and human hematopoietic cells. In summary, the combined results argue in favor of the existence of certain threshold levels for HOXB4 activity that control the differentiation and self-renewal behavior of hematopoietic stem and progenitor cells. Indeed, existing evidence suggests that dosage effects of ectopically expressed transcription factors may be more the rule than an exception.
同源域转录因子HOXB4是体外和体内扩增造血干细胞以及促进体外分化的胚胎干细胞形成造血细胞的最具吸引力的工具之一。然而，在体内，与增强自我更新而不干扰分化的有利作用相兼容的表达水平仍有待确定。在本文中，基于我们实验室和其他实验室的观察结果，即异位HOXB4表达会导致小鼠和人类造血细胞谱系分化的浓度依赖性扰动，我们讨论了定义HOXB4表达“治疗宽度”的必要性。总之，综合结果表明存在某些HOXB4活性阈值水平，可控制造血干细胞和祖细胞的分化及自我更新行为。确实，现有证据表明异位表达的转录因子的剂量效应可能更为常见而非例外。
