TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment.

Source reference: The Journal of clinical investigation • 2025 • DOI: 10.1172/JCI184021 • PMID: 40111422 Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies, and there is an urgent need for the development of improved therapies for TP53-mutant leukemias. Here, we identified mutations in TET2 as the most common co-occurring mutation in patients with TP53-mutant acute myeloid leukemia (AML). In mice, combined hematopoietic-specific deletion of TET2 and TP53 resulted in enhanced self-renewal compared with deletion of either gene alone. Tp53/Tet2 double-KO mice developed serially transplantable AML. Both mice and patients with AML with combined TET2/TP53 alterations upregulated innate immune signaling in malignant granulocyte-monocyte progenitors, which had leukemia-initiating capacity. A20 governs the leukemic maintenance by triggering aberrant noncanonical NF-κB signaling. Mice with Tp53/Tet2 loss had expansion of monocytic myeloid-derived suppressor cells (MDSCs), which impaired T cell proliferation and activation. Moreover, mice and patients with AML with combined TP53/TET2 alterations displayed increased expression of the TIGIT ligand, CD155, on malignant cells. TIGIT-blocking antibodies augmented NK cell-mediated killing of Tp53/Tet2 double-mutant AML cells, reduced leukemic burden, and prolonged survival in Tp53/Tet2 double-KO mice. These findings describe a leukemia-promoting link between TET2 and TP53 mutations and highlight therapeutic strategies to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML. Instructions for use: README Processed Data for "TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment" Citation: J Clin Invest. 2025;135(10):e184021. https://doi.org/10.1172/JCI184021. Instructions for use These processed data can be used to reproduce figures showing scRNA-seq and CITE-seq data from the article referenced above. This data package is meant to be used with an analysis project at https://github.com/blaserlab/lapalombella_pu Steps to reproduce selected figures: 1. System Requirements R v4.4 or greater Rstudio This software has been tested on Linux Ubuntu 22.04.5 Loading the complete dataset occupies approximately 8 GB memory. 2. Installation download this object in a convenient location on your system. clone the analysis project to your computer using git clone https://github.com/blaserlab/lapalombella_pu.git open the R project a list of the packages required for the project can be found in library_catalogs/blas02_lapalombella_pu.tsv. Filter for packages with status == "active". Install these packages and their dependencies. install custom packages from our R Universe repository using these commands: install.packages('blaseRtools', repos = c('https://blaserlab.r-universe.dev/','https://cloud.r-project.org/')) install.packages('blaseRtemplates', repos = c('https://blaserlab.r-universe.dev/,'https://cloud.r-project.org/')) install.packages('blaseRdata', repos = c('https://blaserlab.r-universe.dev/','https://cloud.r-project.org/')) source R/dependencies.R (the final line in that file must be edited to point to the directory containing the data package) source R/configs.R (the file paths defining the output variables should be customized for your system) see the named files in R/ to reproduce specific figures from the manuscript typical time required for the first installation and data loading is approximately 15 minutes. This excludes the time required to download the data package.来源参考文献：《临床研究杂志》（The Journal of Clinical Investigation）• 2025年 • DOI: 10.1172/JCI184021 • PMID: 40111422 TP53基因突变与缺失与髓系恶性肿瘤患者的不良预后密切相关，亟需开发针对TP53突变型白血病的优化治疗方案。本研究明确，TET2突变是TP53突变型急性髓系白血病（acute myeloid leukemia, AML）患者中最常见的共发突变。在小鼠模型中，与单独缺失任一基因相比，造血组织特异性同时敲除TET2与TP53可增强细胞自我更新能力；Tp53/Tet2双基因敲除小鼠可形成可连续移植的AML。同时携带TET2/TP53变异的AML患者与小鼠模型中，恶性粒单核系祖细胞的先天免疫信号通路均被上调，且这类祖细胞具备白血病起始能力。A20通过触发异常的非经典核因子κB（noncanonical NF-κB）信号通路调控白血病维持。缺失Tp53/Tet2的小鼠体内单核细胞样髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）扩增，这类细胞可抑制T细胞的增殖与活化。此外，同时携带TP53/TET2变异的AML患者与小鼠模型中，恶性细胞表面的TIGIT配体CD155表达水平均升高。抗TIGIT抗体可增强自然杀伤细胞（natural killer cell, NK）介导的Tp53/Tet2双突变AML细胞杀伤效果，降低白血病负荷，并延长Tp53/Tet2双基因敲除小鼠的存活时间。本研究揭示了TET2与TP53突变之间的促白血病关联，并提出了针对该不良预后AML亚型的治疗策略，以逆转其免疫抑制性骨髓微环境。 使用说明：README "TP53突变与TET2缺失协同驱动白血病发生并建立免疫抑制微环境"相关处理后数据集 引用信息：《临床研究杂志》（The Journal of Clinical Investigation）. 2025;135(10):e184021. https://doi.org/10.1172/JCI184021. 使用说明 本处理后数据集可用于复现上述参考文献文章中展示单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）与细胞索引转录组和表位测序（CITE-seq）数据的相关图表。本数据包需与https://github.com/blaserlab/lapalombella_pu 处的分析项目配合使用。 复现指定图表的步骤： 1. 系统要求 R 4.4及更高版本 RStudio 本软件已在Linux Ubuntu 22.04.5系统上完成测试。 加载完整数据集约需8 GB内存。 2. 安装步骤 将本数据集对象下载至系统中的任意便捷路径。 使用git clone命令克隆分析项目至本地计算机：git clone https://github.com/blaserlab/lapalombella_pu.git 打开R项目文件 项目所需的软件包列表可在library_catalogs/blas02_lapalombella_pu.tsv文件中查看，筛选出状态为"active"的软件包，安装这些软件包及其依赖项。 使用以下命令从我们的R Universe仓库安装自定义软件包： install.packages('blaseRtools', repos = c('https://blaserlab.r-universe.dev/','https://cloud.r-project.org/')) install.packages('blaseRtemplates', repos = c('https://blaserlab.r-universe.dev/','https://cloud.r-project.org/')) install.packages('blaseRdata', repos = c('https://blaserlab.r-universe.dev/','https://cloud.r-project.org/')) 运行R/dependencies.R脚本（需编辑该脚本的最后一行，使其指向数据集包所在的目录） 运行R/configs.R脚本（需根据您的系统自定义定义输出变量的文件路径） 可通过R/目录下的对应命名文件复现论文中的特定图表 首次安装与数据加载的典型耗时约为15分钟，不包含下载数据集包的时间。