Rosenbauer Frank, Koschmieder Steffen, Steidl Ulrich, Tenen Daniel G
Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Blood. 2005 Sep 1;106(5):1519-24. doi: 10.1182/blood-2005-02-0717. Epub 2005 May 24.
Increasing evidence suggests that leukemias are sustained by leukemic stem cells. However, the molecular pathways underlying the transformation of normal cells into leukemic stem cells are still poorly understood. The involvement of a small group of key transcription factors into this process was suggested by their frequent mutation or down-regulation in patients with acute myeloid leukemia (AML). Recent findings in mice with hypomorphic transcription-factor genes demonstrated that leukemic stem-cell formation in AML could directly be caused by reduced transcription-factor activity beyond a critical threshold. Most interestingly, those experimental models and the paucity of biallelic null mutations or deletions in transcription-factor genes in patients suggest that AML is generally associated with graded down-regulation rather than complete disruption of transcription factors. Here, we discuss the effects of transcription-factor concentrations on hematopoiesis and leukemia, with a focus on the regulation of transcription-factor gene expression as a major mechanism that alters critical threshold levels during blood development and cancer.
越来越多的证据表明，白血病是由白血病干细胞维持的。然而，正常细胞转化为白血病干细胞的分子途径仍知之甚少。急性髓系白血病（AML）患者中一小部分关键转录因子频繁发生突变或下调，提示它们参与了这一过程。最近在转录因子基因低表达的小鼠中的研究发现，AML中白血病干细胞的形成可能直接由转录因子活性降至临界阈值以下所致。最有趣的是，这些实验模型以及患者中转录因子基因双等位基因无效突变或缺失的缺乏表明，AML通常与转录因子的分级下调而非完全破坏有关。在此，我们讨论转录因子浓度对造血和白血病的影响，重点关注转录因子基因表达的调控，这是在血液发育和癌症过程中改变临界阈值水平的主要机制。
