Opposing effects of acute versus chronic inhibition of p53 on decitabine’s efficacy in myeloid neoplasms
Opposing effects of acute versus chronic inhibition of p53 on decitabine’s efficacy in myeloid neoplasms
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DOI：
10.1038/s41598-019-44496-6
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发表时间：
2019-06
影响因子：
4.6
通讯作者：
Moe Tamura;Taishi Yonezawa;Xiaoxiao Liu;S. Asada;Y. Hayashi;T. Fukuyama;Yosuke Tanaka;T. Kitamura-T.-Kitamu
中科院分区：
文献类型：
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作者：
Moe Tamura;Taishi Yonezawa;Xiaoxiao Liu;S. Asada;Y. Hayashi;T. Fukuyama;Yosuke Tanaka;T. Kitamura-T.-Kitamu
地西他滨是一种 DNA 甲基转移酶抑制剂，被认为是治疗 p53 突变骨髓增生异常综合征 (MDS) 和急性髓系白血病 (AML) 的有前途的药物。然而，p53 的缺失是否实际上会增加 MDS/AML 细胞对地西他滨的反应仍不清楚。在这项研究中，我们使用 MLL-AF9 驱动的 AML 和突变 ASXL1 驱动的 MDS/AML 小鼠模型评估了 p53 在地西他滨处理的 MDS 和 AML 细胞中的作用。 MDS/AML 细胞中 CRISPR/Cas9 介导的 p53 消耗并没有增加，反而降低了它们对地西他滨的敏感性。这些细胞中显性失活 p53 片段 (p53DD) 的强制表达也降低了它们对地西他滨的反应，证实 p53 的急性抑制赋予 AML 和 MDS/AML 细胞对地西他滨的耐药性。相比之下，Trp53缺陷小鼠的骨髓祖细胞产生的表达MLL-AF9的AML细胞在体内对地西他滨比野生型细胞更敏感，这表明长期慢性p53缺陷会增加AML细胞对地西他滨的敏感性。总而言之，这些数据揭示了 p53 在调节骨髓肿瘤对地西他滨治疗的反应方面的多方面作用。
Decitabine is a DNA methyltransferase inhibitor and is considered a promising drug to treat myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with p53 mutations. However, whether loss of p53 in fact increases the response of MDS/AML cells to decitabine remains unclear. In this study, we assessed the role of p53 in MDS and AML cells treated with decitabine using mouse models for MLL-AF9-driven AML and mutant ASXL1-driven MDS/AML. CRISPR/Cas9-mediated depletion of p53 in MDS/AML cells did not increase, but rather decreased their sensitivity to decitabine. Forced expression of a dominant-negative p53 fragment (p53DD) in these cells also decreased their responses to decitabine, confirming that acute inhibition of p53 conferred resistance to decitabine in AML and MDS/AML cells. In contrast, MLL-AF9-expressing AML cells generated from bone marrow progenitors ofTrp53-deficient mice were more sensitive to decitabinein vivothan their wild-type counterparts, suggesting that long-term chronic p53 deficiency increases decitabine sensitivity in AML cells. Taken together, these data revealed a multifaceted role for p53 to regulate responses of myeloid neoplasms to decitabine treatment.