ArticleThe Journal of clinical investigation2023
A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Prognostic impact of intensive chemotherapy in patients with TP53-mutated AML.Blood cancer journal · 2026Article
- The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications.Frontiers in immunology · 2026Review
- Article
- THRAP3 promotes ferroptosis resistance in acute myelocytic leukemia through SLU7-mediated alternative splicing of GIT2.Nature communications · 2025Article
- GATA2 decommissioning of enhancers: A mechanism to constrain inflammatory signaling.Cell reports · 2025Article
- Molecular Characteristics and Treatment Implications of TP53 Gain-of-Function Mutations in Non-Small Cell Lung Cancer.Cancer medicine · 2025Article
- Dual mechanism of inflammation sensing by the hematopoietic progenitor genome.Science advances · 2025Article
- From Chemotherapy to Targeted Therapy: Unraveling Resistance in Acute Myeloid Leukemia Through Genetic and Non-Genetic Insights.International journal of molecular sciences · 2025Review
- Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation.Nature communications · 2025Article
- Are TP53 mutations all alike?Hematology. American Society of Hematology. Education Program · 2024Review
- Immunohistochemical Analysis of GATA2 Expression in Endometrium and its Relationship with Hormone Receptor Expression in Benign and Premalignant Endometrial Disorders.Reproductive sciences (Thousand Oaks, Calif.) · 2024Article
- RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives.Blood cancer journal · 2024Review
- Pathogenic GATA2 genetic variants utilize an obligate enhancer mechanism to distort a multilineage differentiation program.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment.Frontiers in pharmacology · 2024Review
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
Abstract
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 NrasG12D/+ p53-/- (NP-/-) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut 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 NPmut-AML transcriptome distinct from that of NP-/- cells. The NPmut-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 NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut 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 NPmut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.
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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.