ArticleJCI insight2020
A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 39 citations in OpenAlex.
- Ultramutagenesis through Combined Msh2 Depletion and Proofreading-Deficient DNA Polymerase ε Expression Enhances Small-Molecule Target Identification in Forward Genetic Screens.ACS chemical biology · 2026Article
- Deficiency in POLE Exonuclease Causes Synthetic Lethality in Highly Aneuploid Cancer Cells.Cancer research · 2026Article
- The DNA damage response and cancer immunotherapy.Nature reviews. Cancer · 2026Review
- Ultramutagenesis through combined Msh2 depletion and proofreading-deficient DNA polymerase ε expression enhances small molecule target identification in forward genetic screens.bioRxiv : the preprint server for biology · 2026Article
- Generation of a stable mouse endometrial tumor-derived cell line using conditional reprogramming.Biological research · 2026Article
- Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models.The Journal of clinical investigation · 2026Article
- A distinct mechanism of epigenetic reprogramming silences PAX2 and initiates endometrial carcinogenesis.The Journal of clinical investigation · 2025Article
- Functions, interactions and prognostic role ofJournal of gynecologic oncology · 2025Article
- Immune Checkpoint Blockade Delays Cancer Development and Extends Survival in DNA Polymerase Mutator Syndromes.Cancer research · 2025Article
- PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans.Database : the journal of biological databases and curation · 2025Article
- Unveiling immunogenic characteristics and neoantigens in endometrial cancer with POLE hotspot mutations for improved immunotherapy.Frontiers in immunology · 2025Article
- Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides.Nature genetics · 2024Article
- Review
- Loss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden.Cancer cell · 2023Article
- Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity.Nature genetics · 2023Article
- The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels.Nucleic acids research · 2022Article
- Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.Nature genetics · 2022Article
- FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity.The Journal of clinical investigation · 2022Article
- Histopathologic diagnosis of endometrial precancers: Updates and future directions.Seminars in diagnostic pathology · 2022Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase ε, the leading strand replicase encoded by POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional LSL-PoleP286R allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following immune checkpoint therapy. This model predicts that human POLE-driven cancers will prove consistently responsive to immune checkpoint blockade. Furthermore, this is a robust and efficient approach to recapitulate in mice the high mutational burdens and immune responses characterizing human cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.