DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo.
DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo.
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DOI：
10.1016/j.ccr.2012.01.021
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发表时间：
2012-04
期刊：
影响因子：
50.3
通讯作者：
S. Takáčová;R. Slany;J. Bártková;V. Stránecký;P. Doležel;P. Lužná;J. Bartek;V. Divoký
中科院分区：
文献类型：
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作者：
S. Takáčová;R. Slany;J. Bártková;V. Stránecký;P. Doležel;P. Lužná;J. Bartek;V. Divoký
MLL-ENL-ERtm癌基因的激活引发骨髓祖细胞的异常增殖。在这里，我们展示了由DNA损伤反应（DDR）机制介导的故障安全机制的诱导，该机制导致ATR/ATM-Chk1/Chk2-p53/ p21cip1检查点的激活和小鼠细胞转化早期由可调节的MLL-ENL-ERtm引起的细胞衰老。此外，我们确定了这种内在抗癌屏障的转录程序，以及ddr诱导的炎症调节因子，这些调节因子可以微调衰老信号，从而以组织环境依赖的方式调节mll - enl永生化细胞的命运。我们的研究结果表明，在mll - enl - ertm介导的转化中，DDR是获得干细胞样特性的限速事件，因为实验抑制该屏障加速了向未成熟细胞状态的转变和急性白血病的发展。
Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21CIP1checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.