Motoda Lena, Osato Motomi, Yamashita Namiko, Jacob Bindya, Chen Lynnette Q, Yanagida Masatoshi, Ida Hiroshi, Wee Hee-Jun, Sun Alfred X, Taniuchi Ichiro, Littman Dan, Ito Yoshiaki
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore.
Stem Cells. 2007 Dec;25(12):2976-86. doi: 10.1634/stemcells.2007-0061. Epub 2007 Sep 6.
The RUNX1/AML1 gene encodes a transcription factor essential for the generation of hematopoietic stem cells and is frequently targeted in human leukemia. In human RUNX1-related leukemias, the RAS pathway is often concurrently mutated, but the mechanism of the synergism remains elusive. Here, we found that inactivation of Runx1 in mouse bone marrow cells results in an increase in the stem/progenitor cell fraction due to suppression of apoptosis and elevated expression of the polycomb gene Bmi-1, which is important for stem cell self-renewal. Introduction of oncogenic N-RAS into wild-type cells, in contrast, reduced the stem/progenitor cell fraction because of senescence, apoptosis, and differentiation. Such detrimental events presumably occurred because of the cellular fail-safe program, although hyperproliferation was initially induced by an oncogenic stimulus. Runx1 insufficiency appears to impair such a fail-safe mechanism, particularly in the stem/progenitor cells, thereby supporting the clonal maintenance of leukemia-initiating cells expressing an activated oncogene. Disclosure of potential conflicts of interest is found at the end of this article.
RUNX1/AML1基因编码一种对造血干细胞生成至关重要的转录因子，在人类白血病中经常成为靶点。在与人类RUNX1相关的白血病中，RAS通路常常同时发生突变，但其协同作用机制仍不清楚。在此，我们发现小鼠骨髓细胞中Runx1失活会导致干/祖细胞比例增加，这是由于细胞凋亡受到抑制以及对干细胞自我更新很重要的多梳基因Bmi-1表达升高所致。相反，将致癌性N-RAS导入野生型细胞会因衰老、凋亡和分化而使干/祖细胞比例降低。尽管致癌刺激最初会诱导细胞过度增殖，但这些有害事件可能是由于细胞的故障安全程序所致。Runx1功能不足似乎会损害这种故障安全机制，尤其是在干/祖细胞中，从而支持表达活化致癌基因的白血病起始细胞的克隆维持。潜在利益冲突披露见本文末尾。
