PKR inhibits the DNA damage response, and is associated with poor survival in AML and accelerated leukemia in NHD13 mice
PKR inhibits the DNA damage response, and is associated with poor survival in AML and accelerated leukemia in NHD13 mice
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DOI：
10.1182/blood-2015-03-635227
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发表时间：
2015-09-24
期刊：
影响因子：
20.3
通讯作者：
May, W. Stratford
中科院分区：
文献类型：
--
作者：
Cheng, Xiaodong;Byrne, Michael;May, W. Stratford
干扰素诱导的双链RNA活化蛋白激酶(PKR)在急性白血病和实体瘤中的表达增加已有报道，但其作用尚不清楚。目前，我们的研究结果表明，急性髓系白血病(AML)患者CD34(+)细胞中PKR的高表达与患者较差的生存和较短的缓解期相关。值得注意的是，我们发现PKR具有一种新的、以前未知的核功能，可以抑制DNA损伤反应信号和双链断裂修复。核PKR通过依赖于蛋白磷酸酶2A的活性来拮抗共济失调-毛细血管扩张突变(ATM)的激活。因此，抑制PKR的表达或活性可以促进电离辐射后ATM的激活、γ-H_2AX的形成和NBS1的磷酸化。PKR转基因而不是PKR缺失的小鼠表现出突变子的表型，其特征是辐射诱导和年龄相关的基因组不稳定，这种不稳定可以被短期的药物抑制部分逆转。此外，在Nup98-Hoxd13(NHD13)小鼠白血病进展模型中，PKR转基因的共表达显著增加了与年龄相关的体细胞突变的积累，而PKR表达的敲除或药物对PKR活性的抑制降低了体内自发突变的频率。因此，PKR与NHD13转基因协同作用加速了白血病的进展，缩短了生存期。综上所述，这些结果表明，核PKR增加具有致癌功能，促进潜在有害突变的积累。因此，抑制PKR可能是防止白血病进展或复发、改善临床结果的一种有用的治疗策略。
Increased expression of the interferon-inducible double-stranded RNA-activated protein kinase (PKR) has been reported in acute leukemia and solid tumors, but the role of PKR has been unclear. Now, our results indicate that high PKR expression in CD34(+) cells of acute myeloid leukemia (AML) patients correlates with worse survival and shortened remission duration. Significantly, we find that PKR has a novel and previously unrecognized nuclear function to inhibit DNA damage response signaling and double-strand break repair. Nuclear PKR antagonizes ataxia-telangiectasia mutated (ATM) activation by a mechanism dependent on protein phosphatase 2A activity. Thus, inhibition of PKR expression or activity promotes ATM activation, gamma-H2AX formation, and phosphorylation of NBS1 following ionizing irradiation. PKR transgenic but not PKR null mice demonstrate a mutator phenotype characterized by radiation-induced and age-associated genomic instability that was partially reversed by short-term pharmacologic PKR inhibition. Furthermore, the age-associated accumulation of somatic mutations that occurs in the Nup98-HOXD13 (NHD13) mouse model of leukemia progression was significantly elevated by co-expression of a PKR transgene, whereas knockout of PKR expression or pharmacologic inhibition of PKR activity reduced the frequency of spontaneous mutations in vivo. Thus, PKR cooperated with the NHD13 transgene to accelerate leukemia progression and shorten survival. Taken together, these results indicate that increased nuclear PKR has an oncogenic function that promotes the accumulation of potentially deleterious mutations. Thus, PKR inhibition may be a therapeutically useful strategy to prevent leukemia progression or relapse, and improve clinical outcomes.