We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in Nras^G12D/+ p53^–/– (NP^–/–) mice, Nras^G12D/+ p53^R172H/+ (NP^mut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NP^mut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an NP^mut-AML transcriptome distinct from that of NP^–/– cells. The NP^mut-AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NP^mut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NP^mut AML cells were sensitive to MEK and NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB–inhibitory protein IκBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NP^mut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.

中文翻译：

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功能获得性p53突变体与致癌NRAS协同作用促进小鼠急性髓系白血病


我们之前证明，同时存在 RAS 通路和 TP53 突变的急性髓系白血病 (AML) 患者的一个子集预后极差，并且大多数 TP53 突变是错义突变。在这里，我们报告说，与 Nras ^G12D/+ p53 ^–/– (NP ^–/– ) 小鼠中发生的混合 AML 和 T 细胞恶性肿瘤相比，Nras ^G12D/+ p53 ^R172H/+ (NP ^mut ) 小鼠迅速发展为炎症相关的 AML。在炎症条件下，尽管 MEK/ERK 过度激活，NP ^mut 造血干细胞和祖细胞 (HSPC) 仍表现出骨髓生成和淋巴细胞生成失衡，且细胞增殖大多正常。 RNA-Seq 分析显示，致癌 NRAS 信号传导和突变 p53 协同作用，建立了与 NP ^–/– 细胞不同的 NP ^mut -AML 转录组。 NP ^mut -AML 转录组显示 GATA2 下调并升高炎症基因的表达，包括与 NF-κB 信号传导相关的基因。 NF-κB 在人类 NRAS TP53 AML 中也上调。人 NP ^mut KY821 AML 细胞中外源表达 GATA2 下调炎症基因表达。小鼠和人 NP ^mut AML 细胞对体外 MEK 和 NF-κB 抑制敏感。蛋白酶体抑制剂硼替佐米可稳定 NF-κB 抑制蛋白 IκBα，减少炎症基因表达，并增强 MEK 抑制剂对 NP ^mut 小鼠的生存益处。我们的研究表明，p53 结构突变体与致癌 NRAS 协同作用，通过与 p53 缺失不同的机制促进 AML。