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.