Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis
Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis
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DOI：
10.1182/blood-2009-07-232249
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发表时间：
2010-02-25
期刊：
影响因子：
20.3
通讯作者：
Ito, Yoshiaki
中科院分区：
文献类型：
--
作者：
Jacob, Bindya;Osato, Motomi;Ito, Yoshiaki
RUNX1/AML1基因是人类白血病中最常见的突变基因。在成年小鼠中，RUNX1的条件性缺失会导致作为白血病靶细胞的造血干细胞(HSCs)的增加；然而，RUNX1(-/-)小鼠不会发生自发性白血病。在这里，我们显示RUNX1(-/-)HSC的维护受到损害，逐渐导致HSC耗尽。在白血病的发展中，干细胞的枯竭可以通过额外的基因变化来挽救。逆转录病毒插入突变显示，Evi5的激活是一种协同的基因改变，EVI5的过表达确实阻止了小鼠RUNX1(-/-)HSC的耗竭。此外，EVI5在人类RUNX1相关白血病中经常过表达。这些结果为白血病前期干细胞的维持机制提供了洞察力，并可能为治疗应用提供新的方向。(血。2010；115：1610-1620)
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 preleukemic stem cells and may provide a novel direction for therapeutic applications. (Blood. 2010;115:1610-1620)