由于 Runx1 缺乏导致的干细胞衰竭在白血病发生中可通过激活 Evi5 来预防。
Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis.
机构信息
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore.
出版信息
Blood. 2010 Feb 25;115(8):1610-20. doi: 10.1182/blood-2009-07-232249. Epub 2009 Dec 14.
Abstract
The RUNX1/AML1 gene is the most frequently mutated gene in human leukemia. Conditional deletion of Runx1 in adult mice results in an increase of hematopoietic stem cells (HSCs), which serve as target cells for leukemia; however, Runx1(-/-) mice do not develop spontaneous leukemia. Here we show that maintenance of Runx1(-/-) HSCs is compromised, progressively resulting in HSC exhaustion. In leukemia development, the stem cell exhaustion was rescued by additional genetic changes. Retroviral insertional mutagenesis revealed Evi5 activation as a cooperating genetic alteration and EVI5 overexpression indeed prevented Runx1(-/-) HSC exhaustion in mice. Moreover, EVI5 was frequently overexpressed in human RUNX1-related leukemias. These results provide insights into the mechanism for maintenance of pre-leukemic stem cells and may provide a novel direction for therapeutic applications.
摘要
RUNX1/AML1 基因是人类白血病中最常发生突变的基因。条件性敲除成年小鼠中的 Runx1 会导致造血干细胞（HSCs）增加，而 HSCs 是白血病的靶细胞；然而，Runx1(-/-) 小鼠不会自发发生白血病。在这里，我们表明 Runx1(-/-) HSCs 的维持受到损害，逐渐导致 HSC 耗竭。在白血病发展过程中，干细胞耗竭可通过额外的遗传变化得到挽救。逆转录病毒插入诱变显示 Evi5 激活是一种合作的遗传改变，EVI5 的过表达确实可以防止 Runx1(-/-) HSC 在小鼠中耗竭。此外，EVI5 在人类 RUNX1 相关白血病中经常过表达。这些结果为维持白血病前干细胞的机制提供了深入的了解，并可能为治疗应用提供新的方向。
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