C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells
C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells
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DOI：
10.1038/leu.2011.202
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发表时间：
2012-02
期刊：
影响因子：
11.4
通讯作者：
Yusuke Satoh;I. Matsumura;Hirokazu Tanaka;H. Harada;Y. Harada;K. Matsui;Masaru Shibata;M. Mizuki-M.-Miz
中科院分区：
文献类型：
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作者：
Yusuke Satoh;I. Matsumura;Hirokazu Tanaka;H. Harada;Y. Harada;K. Matsui;Masaru Shibata;M. Mizuki-M.-Miz
在急性髓性白血病（AML）和骨髓增生异常综合征（mds）中发现了RUNX1的功能缺失突变。尽管有几篇报道表明RUNX1作为肿瘤抑制因子，但其确切功能尚不清楚。在小鼠模型中，由于RUNX1基因本身的改变不会导致白血病的发生，因此白血病的发生需要额外的突变。在这里，我们报道了RUNX1的c端缺失突变体RUNX1dC，减弱了造血干细胞/祖细胞中的dna损伤修复反应。在稳态和γ射线处理后，在runx1dc转导的谱系- Sca1+ c-kit+(LSK)细胞中，γ- h2ax焦点（表明DNA双链断裂的存在）比模拟转导的LSK细胞中积累得更多。实时pcr表达谱分析显示，RUNX1dC可抑制DNA胁迫传感器Gadd45a的表达。此外，携带RUNX1- c末端突变的MDS/AML患者骨髓细胞的GADD45A表达水平显著低于携带RUNX1野生型的MDS/AML患者。对于这一机制，我们发现RUNX1直接调控GADD45A的转录，并且RUNX1和p53协同激活GADD45A的转录。总之，这些结果表明，RUNX1突变导致的Gadd45a功能障碍可能导致多步骤白血病发生所需的额外突变。
Loss-of-function mutations of RUNX1 have been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Although several reports have suggested roles for RUNX1 as a tumor suppressor, its precise function remains unknown. Because gene alterations of RUNX1 by themselves do not lead to the development of leukemia in mouse models, additional mutation (s) would be required for leukemia development. Here, we report that the C-terminal deletion mutant of RUNX1, RUNX1dC, attenuates DNA-damage repair responses in hematopoietic stem/progenitor cells. γH2AX foci, which indicate the presence of DNA double-strand breaks, were more abundantly accumulated in RUNX1dC-transduced lineage− Sca1+ c-kit+(LSK) cells than in mock-transduced LSK cells both in a steady state and after γ-ray treatment. Expression profiling by real-time-PCR array revealed RUNX1dC represses the expression of Gadd45a, a sensor of DNA stress. Furthermore, bone marrow cells from MDS/AML patients harboring the RUNX1-C-terminal mutation showed significantly lower levels of GADD45A expression compared with those from MDS/AML patients with wild-type RUNX1. As for this mechanism, we found that RUNX1 directly regulates the transcription of GADD45A and that RUNX1 and p53 synergistically activate the GADD45A transcription. Together, these results suggest Gadd45a dysfunction due to RUNX1 mutations can cause additional mutation (s) required for multi-step leukemogenesis.